Welcome to Re: Life 👋 !

I’m Aaryan—a junior at Stanford diving headfirst into a world of virology, philosophy, and mild sleep deprivation.

You just stumbled into the weird corner of the internet where I chronicle my life. In each post, I share three brief updates, two quick resources, and one idea to reflect on for the week.

Let’s begin.

🎬 Three Brief Updates 🎬

// Earlier this month, I published my first two research articles in the American Society of Microbiology (ASM) (1,2)! For longtime readers, these papers are the culmination of my two-year adventure to discover new therapeutic viruses in nature.

After four rounds of peer review—and nearly abandoning these papers—all I can convey is nostalgia and relief. Thank you so much to Drs. Paul Bollyky, Jessica Sacher, and Zachary Flamholz for guiding and co-authoring this work with me.

// In a classic case of short-term amnesia, I’m now wrapping up a new paper studying how bacterial viruses behave in lungs with cystic fibrosis. Meanwhile, I’m (quite literally) cooking up a secret project from my home in Los Angeles. I’ll leave you with a picture for now, but more on this to come…

// As my summer at Armata Pharma wraps up, I’m savoring my final marches around LA. Since my last note, I’ve road-tripped across Malibu, witnessed Spain’s world-cup victory while eating streetside tacos, and (finally) laid eyes on Odilon Redon’s sketches at the Getty.

🎉 Two Quick Links 🎉

Earth’s First Synthetic Viruses
Researchers at the Arc Institute have used LLMs to design therapeutic viruses unseen in nature. Shoutout to the Hie Lab and my friend Samuel King, who recently published this work in Science.


Z Fellows
Spend a week in San Fransisco. Receive mentorship from founders and engineers. Get $10,000 to build what’s meaningful to you.

🧠 One Simple Idea 🧠

Antoine de Saint-Exupéry on the art of starting anything:

“If you want to build a ship, don’t drum up the men to gather wood, divide the work, and give orders. Instead, teach them to yearn for the vast and endless sea.”

Work does not begin with motion, but with the will to move.

To start walking, you must first chase down the desire to walk.

Question for the week: how can I notice my will and steer it closer to what’s meaningful?

see you soon,
- aaryan

Welcome to Re: Life 👋 !

I’m Aaryan—a junior at Stanford diving headfirst into a world of virology, philosophy, and mild sleep deprivation.

You just stumbled into the weird corner of the internet where I chronicle my life. In each post, I share three brief updates, two quick resources, and one idea to reflect on for the week.

Let’s begin.

🎬 Three Brief Updates 🎬

// Spring has come and left. After packing my room, contending with BIOE42 finals, and delivering my first ever TEDx talk (?!), I’ve somehow emerged from the rubble as a rising senior. Once again, I’m forced to recognize that another year has passed at Stanford, and I can’t help but smile at the fun of it all.

// Last month, I hopped onto a plane bound for Los Angeles and started my life from scratch. Specifically, I’m here to work on R&D with a phage therapy company called Armata Pharmaceuticals.


Stepping into industry has jolted me awake. As we refine our science and blast toward our first phase III clinical trial, I remember why I wanted to become a bioengineer. Every day is new here, so stay tuned for more!

// Meanwhile, I’m ironing out life and making sense of this sprawling, unfamiliar city. So far, I’ve walked the Santa Monica pier, perfected my grocery route at Food4Less, and devoured burritos on Jefferson street (naturally, squatting next to a hundred roaring customers as Norway vs. Brazil played on a janky outdoor TV).


Frankly, LA doesn’t feel real, and I love it.

🎉 Two Quick Links 🎉

Why Is this Liquid Attracted to Blood?
A deceptively simple question about liquids that led to an entire PhD thesis on fluid dynamics.

Google Gemini XPRIZE
A $2M hackathon for people building in AI. (Without a hint of sarcasm, I’m confident at least one of our readers could sweep this whole challenge).

🧠 One Simple Idea 🧠

One of my favorites from Leo Rosten:

“I learned that it is the weak who are cruel, and that gentleness is to be expected only from the strong.”

Strength, when used beautifully, becomes peace.

This week, I’m asking myself: How can I channel my force into something beautiful?


see you soon,
- aaryan

In my past two years at Stanford Medicine, I enjoyed what might be the coolest job on the planet.

You see, there was no formal name for my line of work.

But if I had to pick, perhaps “microbe hunter” would best capture the spirit.

My mission was simple: to explore nature for rare and interesting viruses.

By morning, I’d snap on my gloves and trap viruses in the wild. By night, I’d spin out their DNA, poke them under microscopes, and burn sleepless hours naming each one.

Chasing viruses educated me in many ways—about myself, about microbes, about the immensity of life. But it also initiated me to many of the gaps in modern biology.

And there was one gap in particular that haunted me endlessly.

A Portrait of Modern Sequencing

After isolating a virus, my mission was to sequence its DNA and prove it was unique.

Four days earlier, I’d email my supervisor to send an email to our sequencing company. The sequencing company would then email back, asking for a grant code to cover their fees.

After another email chain with Stanford, the sequencing company finally would send us forms to print out, sign, and store neatly in a ziploc bag with each sample in a fresh container of dry ice.

And only then—after a whole week of seemingly paranormal exercises—could we begin to extract DNA from our viruses, and mail them to a suburban town halfway across the country. All so our data could arrive several weeks after that—in yet another poorly-formatted email.

Were there other ways to sequence DNA? Perhaps, but not without their costs.

We could have bought a DNA sequencer, but even standard machines ran upwards of $100K USD.

Meanwhile, quicker sequencing companies failed to process our viruses entirely—often returning unusable data and wasting weeks of time.

My mishaps with sequencing may have been specific, but they pointed to a much wider flaw.

I couldn’t believe it. DNA sequencing was supposed to be the backbone of biology.

But today’s sequencers resembled mainframes from the 1960s. And any attempt to outsource sequencing felt like a medieval ghost summoning.

After decades of technology, we still didn’t have a world-class way to read biology.

Through my work, I had seen the flaws of sequencing up close.

But when I looked around, no one seemed to care.

That whole week—in class, on my bike, between bites of lunch—I couldn’t think straight. I wondered if I was dense.

Sequencing was the tool of our trade. Surely I wasn’t the first person to notice that it made no sense?

But from deep within, there was another question that clung to me desperately.

What if we sequence DNA anywhere, instantly, for the price of electrons?

And what kind of fantastic future would emerge if we could?

The Labyrinth of Life

As I’m sure you’ve noticed by now, this article was never about virology.

Sequencing DNA isn’t just a chemical exercise. It represents the grandest quest in biology—to lay out the language of life, and to elucidate the rules of our existence.

I’ve always viewed biology as a labyrinth.

As scientists (and as people), we find ourselves standing at the gates of the world’s grandest maze—home to creatures and alchemy that defy human knowledge.

In some sense, the entire history of biology is a record of our first steps into this labyrinth.


We discovered Taq polymerase in a hot spring. We isolated GLP-1 from gila monsters, and rhodopsins from unsuspecting jellyfish. We encountered tardigrades and giant viruses and bacteria that could gobble up rust for food1.

Can you believe it? This is our world!

Life is vast, and it remains painfully mysterious.

Somewhere, deep within the labyrinth of life, is our next generation of brilliant biology. Resting within its walls are answers to humanity’s most intimidating challenges.

If we’ve found so much from feeling in the dark, what if we could illuminate everything?

This is what makes sequencing meaningful.

The labyrinth of life is made from DNA. Reading it is our only path forward, to reach the countless answers that lie within2.

And any effort to improve this process is an effort that nurtures our entire field.

The Stakes of Tools

As a biologist, I will always believe in the beauty of life, and its infinite potential.

If we’ve fallen short, we aren’t being limited by biology. We’re being limited by what we can make and measure.

DNA is the basic unit of life. If we hone sequencing to its limit, biology will bloom into its true potential.

If you read the history of science, you’ll notice a pattern: we tend to separate inventions from the tools that enable them.

We learn, for instance, that William Shockley developed the modern transistor. We learn that Fermi et al. built the first nuclear reactor, and that Virchow and Hooke proposed cell theory.

It’s easy to trace scientific progress back to brilliant scientists.

It’s much harder to see negative space—to appreciate the invisible ladder of tools that science quietly rests on.

We forget that Shockley’s transistor was made possible by germanium chemistry. We forget that nuclear reactors wouldn’t work without control rods, and that cell theory wasn’t even reasonable until the invention of the microscope.

To borrow the words of David Foster Wallace: we are fish, and tools are water.

Tools are transparent, and yet they are the medium through which we observe reality. They quietly decide what is visible and invisible to humanity.

Most biologists find tools boring, and with good reason.

When you work a pipette for long enough, it becomes as familiar and obvious as your own hand. When you sequence DNA your whole life, it’s hard to imagine another way of reading biology.

But this is why I find tools exhilarating—because the right tool can burst open entirely new ways of thinking. Because the right tool at the time can change fate itself.

Talk to (almost) any biologist, and you’ll sense their enthusiasm for the world. It’s a remarkable time to be thinking about life, and we’re all sitting at the edge of a remarkable future.

Reforming sequencing will reform all of biology, and it is what will throw us over the edge.

The New Eyes of Biology

I believe in DNA, and in our reckless, immortal adventure to read life.

I believe that sequencing is the most important problem in biology—one that is downstream of all the questions and answers we could ever ask.

It’s a strange, intoxicating clarity. I’m convinced that there is nothing more meaningful and interesting I could be doing with my time.

So why wait? Why falter?

For the past six months, I’ve embarked on a self-directed expedition through the land of sequencing.

Over nights and weekends, I built a foundation in polymer chemistry, signal processing, and nano-fabrication. I pored over the works of Frederick Sanger, and the lab notes of David Deamer that grew into Oxford Nanopore3.

With pencil and paper, I retraced our history of reading DNA—all the way from ddNTP base termination to single-molecule fluorescent chemistry. And I furiously studied our leading commercial sequencers—right down to their ASICs and flow cells—to learn their systems and design around their faults.

Along the way, I’ve encountered many of the rules and limits that govern sequencing. But I’ve found just as much faulty logic, and just as many assumptions that have gone unquestioned for decades.

My dream is to forge the world’s leading DNA sequencer—with state-of-the-art accuracy, supersonic turnaround, and the best per-base economics that physics allows.

With my background in bioengineering (and my personal stake in sequencing), I’ve developed a working theory on how to make this happen. And with support from OSV and Emergent Ventures, I’m running experiments to ground this mechanism in reality.

Molecules are ephemeral. But life will forever change our universe.

This work may deal with DNA, and perhaps it will grow into much more.

But it will always be an odyssey to make sense of life—to cast our hands a little further into this incredible world.

Maybe something’s wrong with me. I see so much beauty here, and so much potential.

It’s been a while since I’ve felt so alive.

And whatever the journey, I can’t shake the sense that we’re headed someplace exciting.

stay tuned,
- aaryan

Welcome to Re: Life 👋 !

I’m Aaryan—a junior at Stanford diving headfirst into a world of virology, philosophy, and mild sleep deprivation.

You just stumbled into the weird corner of the internet where I chronicle my life. In every post, I share three brief updates, two quick resources, and one idea to reflect on for the week.

Let’s begin.

🎬 Three Brief Updates 🎬

// April’s here, and I’m back at Stanford after a blindingly quick spring break. Some notable achievements include: competing in our state-wide karate tournament, earning my full driver’s license (finally!), and sleeping sixteen out of twenty-four hours in a day.

// Lately, I’ve been fascinated by DNA sequencing (after discovering nearly all its flaws in my research with viruses). Sequencing is our central tool in biology, and I’m thinking about how to accelerate it with solid-state chemistry instead of biological machinery.

When I’m not in class, I’m teaching myself signal processing math, nanofab design (i.e. for e- beam lithography) and the polymer chemistry of DNA. More on this soon!

// Other than that, I’m busy making the most of my favorite season. So far, I’ve enjoyed catching up with friends, sleeping outside (on actual real-life grass), diving into labwork, and practicing karate in the sun.

I guess we don’t need very much to be happy :)

🎉 Two Quick Links 🎉

Perplexity AI Fellowship
A $220K fellowship for interdisciplinary thinkers. No PhD required.


The Wildest Scatter Plot I’ve Seen This Year
Apparently, a human on a bicycle is more energy-efficient than any animal ever recorded.

🧠 One Simple Idea 🧠

American philosopher Howard Thurman on passion:

“Don’t ask what the world needs. Ask what makes you come alive, and go do it. Because what the world needs is people who have come alive.

Taking the next step isn’t a matter of clarity, but of action.

If you’re honest, you’ll already know your answer.

Take your little step.

on y va,
- aaryan

Welcome to Re: Life 👋 !

I’m Aaryan—a junior at Stanford diving headfirst into a world of virology, philosophy, and mild sleep deprivation.

You just stumbled into the weird corner of the internet where I chronicle my life. In every post, I share three brief updates, two random lessons, and one idea to reflect on for the week.

Let’s begin.

🎬 Three Brief Updates 🎬

// March has unfolded, and I’m writing under the shadow of finals season on campus. Notably, since my last post, I helped organize Stanford’s yearly Japan Exchange Conference (SJEC) and guided my international friends through the halls of Costco (thank you to the whole team and all our students!!)

// Lately, in my medical radiography class, I’ve been learning about k-spaces and MRI image formation. I also had the chance to explore Stanford’s medical cyclotron facility (huge thanks to Dr. Butts-Pauly for making this possible)!


// In my pockets of free time, I’ve been reading The Art of Wordly Wisdom, hunting for more viruses, and (unfortunately) playing online chess. Life, at least for now, has a way of becoming more and more interesting…

🎉 Two Little Lessons 🎉

Eigen Grants
A $100K grant for ambitious people building their passion projects


What DNA Actually Looks Like
If you could hold DNA in your hand, what would it look like? Well, I took a picture!

🧠 One Simple Idea 🧠

French Philosopher Simone Weil on the nature of giving:

Attention is the rarest and purest form of generosity.

Every encounter in your life is an opportunity to give yourself infinitely—to your loved ones, to the world, to the moment you’re in.

Why not begin today?

Keep dreaming,
Aaryan

Welcome to Re: Life 👋 !

I’m Aaryan — a junior at Stanford diving headfirst into a world of virology, philosophy, and mild sleep deprivation.

You just stumbled into the weird corner of the internet where I chronicle my life. In every post, I share three brief updates, two random lessons, and one idea to reflect on for the week.

Let’s begin.

🎬 Three Brief Updates 🎬

// At Stanford, winter quarter means rain, and rain means everyone on campus holes up indoors (to finish their homework). These days, I’ve been living out of my room—currently reviewing the physics of MRI imaging and recovering from my latest exam on electromagnetism.


// Spontaneously participated in Stanford TreeHacks, built a $10 optical sensor to detect bacteria in contaminated water. (The precision is still horrible but I’m working on it)!

// Learning Japanese, reading some classics (recent hits include Candide, Giovanni’s Room, and Flowers for Algernon). Also preparing for an upcoming karate tournament back in Sudbury!

🎉 Two Little Lessons 🎉

Make Something Heavy
Huge shoutout to Pranav Menon for sending this my way. Best read this month.

The Artist that Saw Ultraviolet
How Claude Monet’s strange eyes revolutionized impressionism

🧠 One Simple Idea 🧠

American author Charles Bukowski on agency:

“I was waiting for something extraordinary to happen but as the years wasted on nothing ever did unless I caused it.”

The only miracle in this world is your own will.

What will you do with it?

Happy holidays,
Aaryan

*p.s. Huge shoutout to Esugen for choosing the cover photo (and being a top-notch radiology classmate)!

I turned twenty last week.

Sure, days and years might just be random slices of time, but this still feels significant.

When my birthday came, it felt like sitting at the ledge of a towering cliff—wind in my eyes, legs dangling over, squinting past the sun and into a blindingly large world. I never knew the turn of a single day could be so exhilarating, and so intimidating.

With a fresh decade in hand, it feels right to consider all the days that now trail behind me.

When I was a kid, I thought my voice didn’t matter.

I don’t mean this pathologically. It’s just hard to walk through your whole childhood without a sprinkling of insecurity.

As humans, we are born powerless and owe our survival to the grace of those before us. When you’re tugged by your elders through the foreign and frightening world, it’s only natural to defer to their judgment.

Their answers may not be absolute, but they are as correct as they need to be for the moment we’re in. We all grow by looking upwards, to the faces of those who raised us, by asking for a thousand permissions, by stretching our arms and stumbling towards clarity.

Adulthood is a miracle. After the blinding landscape of childhood, you find yourself at a clearing, alone. And it dawns on you that you’re approaching the age of your own parents when they had you. It occurs to you that you’re now as old as the people who had all the answers.

Somewhere, along the mist-laden trail of your life, you will step past this singularity, and life will never be the same.

I don’t mean to say you’re losing anything, either. Not at all! As your childhood flutters away, a world of finer and more fascinating things starts coming into view.

When I was a kid, I thought my voice didn’t matter. And it’s true. When you’re young, you can get away with saying nearly anything. No dream is too high-strung, no insult is too fatal to cause lasting damage. It’s a fleeting sort of invincibility: the children build and destroy everything with their words, and the adults knowingly smile on.

Adulthood, to me, is the trembling realization—and acceptance—of your power as a person.

With each month, it becomes clearer that I’m not invincible. No one is. I look around and realize that everyone is made of the same flesh and bones and their own handful of dreams. It all seems so simple, so searingly true, and I wonder what sort of blanket I was sitting under my entire life.

With the awareness of adulthood, I’ve become achingly aware—of my capacity to inflict pain, and the ceaseless possibility of being hurt by others.

All at once, I see the universe of ways I can flourish, create, and make life beautiful. My choices are no longer weightless. My place in the greater story of things is real, and worth taking seriously.

When we were kids, we dreamt all the time about who we wanted to be. We weren’t scared to face the immensity of our potential.

So now that we’ve reached the stream—now that we’ve run and stumbled and seen the full face of life—let’s not forget the task at hand.

The only way to answer that ultimate question, of who you are, of who you want to become, is to paint it through your life.

I don’t believe we came all this way just to grow up. Adulthood must merely be the opening bell. Now that we’ve read the rules, life is finally asking us to stand for something.

Somewhere in my heart, I’ve come to terms with my potential—for joy, for pain, for the countless emotions that make life real. And I see that there is nowhere for my dreams to flow except into my life. I must become the instrument to express my own convictions.

It‘s the one thing in the world only I can do, and by far the most precious.

I don’t claim to know more, just more than myself since last sunset. We’re all left to change, to ripen and bloom with the passing days, as the sky fades to white, and the old clouds faintly steal the air of other days.

In the meantime, all we can do—all we could ever do—has never changed. Inhale, exhale, and hold life carefully as it spins from this day, to the next, to the next…and perhaps somewhere beyond.

Let’s turn our time into something beautiful

-Aaryan

Welcome to Re: Life 👋 !

I’m Aaryan — a junior at Stanford diving headfirst into a world of virology, philosophy, and mild sleep deprivation.

You just stumbled into the weird corner of the internet where I chronicle my life. In every post, I share three brief updates, two random lessons, and one idea to reflect on for the week.

Let’s begin.

🎬 Three Brief Updates 🎬

// Autumn quarter is a wrap! After some monstrous finals, Christmas festivities, and a restful flight from SFO, I’m finally home in Sudbury.

We’re somehow halfway into winter break, but I’m glad to enjoy my last weeks with friends, family, and nostalgic Christmas movies (which really means: Home Alone 1 and 2, and nothing else).

// After a frantic year hunting for new viruses, I’m putting the final strokes on my phage research. With support from my lab at Stanford, I’m finishing up a manuscript on my research, currently bound for a journal in the American Society of Microbiology. Huge shoutout to my mentor (Dr. Jessica Sacher) and my PI (Dr. Paul Bollyky) for making this possible!


// Spending the rest of my hours walking, napping, and chronicling my philosophy on substack. Also flipping through some long-awaited books on my shelf: Microbe Hunters, Matilda, and The Invention of Morel (masterpiece)!

🎉 Two Little Lessons 🎉

Airplane “Vibing”
Honestly one of the strangest engineering effects I’ve seen…

The Telegraph Tree
How a plant in Malaysia changed the world, then fell into obscurity.

🧠 One Simple Idea 🧠

Some effortless wisdom from Cormac McCarthy:

You never know what worse luck your bad luck has saved you from.

What better time than today to smile at life?

Happy holidays,
Aaryan

Lately, the world has convinced itself that ambition equals pain.

I’m not sure exactly when this began. I just recall that, all of a sudden, everyone everywhere started glorifying their pain. It seems that hordes of people online are now flashing sleeplessness and slavish workdays like high-fashion—as if having some grand, planetary mission magically justifies self-abuse1.

I’m not sure where this came from, but it has infiltrated us completely. It’s now hard to listen or speak about anyone’s dreams without the idea bubbling up unwittingly. This gambit of pain and gain—the notion that we must sacrifice happiness to feel valued—is now pervasive2.

Perhaps I’m being selfish, but I’ve never understood this. In fact, I’d take it a step further and question if the tradeoff even exists.

Is everyone ultimately forced to choose between ambition or fun? What if your life could be ambitious AND fun?

In any case, I think the popular outlook is false and unhealthy.

First: There are 24 hours in a day. Even with a day job, family, and enough breathing room to sleep and laugh and be human, most of us still have several hours left to chisel our dreams into shape3. The time is certainly there—it’s just too scattered to be useful, or vanishes when we say yes to too many things4. So when we claim that our dreams force us to neglect the rest of life, we’re really pointing to poor prioritization. With tighter intentions and habits, you can work miracles with the same day.

Second: You risk wasting your energy. When you conflate success with pain, you’ll end up believing that your journey must be difficult. Often, this means you’ll ignore the shortest path to your destination because it’s too easy (“this feels like cheating!”). In reality, there’s no glory in breaking your back where a finger would suffice. Reaching your goals with the least movement isn’t cheating—it’s a mark of elegance.

Third: Fun is an eternal choice. If it were in your control, would you carry out your life’s work in joy or despair? The catch, of course, is that you’re always in control. History’s most celebrated humans weren’t born masters. They loved their craft so profoundly that pain itself became small. Fortunately, this mindset is accessible to every human on the planet. With trained eyes, there is infinite beauty to be found in any craft. With deliberate practice, everything can become a game—life itself can become play.

In short, I think the binary of growth and suffering is fake.

We can transcend this tradeoff.

There’s no glory in pain for its own sake. There is only room for glory in our response.

From birth, we’re destined to the same fate: to live, to stumble, to confront our own universe of problems.

When we accept problems as a rule, we can learn to savor the game of life. We can learn to walk into pain without seeking it.

This is our highest potential. As humans, we can (and should) strive to grow happily.

Some day, you will revisit your life—not through its outcomes, but through its moments. When this day comes, I hope you’ll smile at your moments, too.

Yours truly,
Aaryan

Footnotes

These days, I’m paying more attention to what matters in life. As a result, I’m paying attention to what doesn’t matter.

Across time and culture, there’s a common idea that the material world is an illusion1. It’s thought that people, places and perceptions are effectively the hallucinations of our mischievous hearts.

But if everything outside us is fickle, what’s real?

The answer must be our mind. Even as a proud scientist, I concede that objective reality is misleading.

No measurement or impression of ours can be objective so long as it filters through the gates of perception.

History shows that the mind can warp reality to its will. Centuries ago, the so-called “objective” truths of vitalism and geocentricity proved this effect. To say that we’re overcome these biases even today would be foolish. We can not strip our minds from how we see life. Nothing escapes its grasp.

What am I trying to say here?

If the mind is crucial to our worldview, it must also be true that controlling your mind is the ultimate art.

Reality is outside the question. But your mind can certainly make heaven and hell from the same situation.

It’s a trivial thought, yes, but trivial thoughts are often timeless thoughts. It helps to recall that nothing you experience is real outside of yourself.

The universe you experience is merely a reflection of your mind.

This is worth reading twice. The universe you experience is merely a reflection of your mind.

Your reality, then, is negotiable. All of your pleasure and pain can be traced back to you, and you alone.

As a martial artist, I’m fortunate that we trained our minds as intensely as we did our limbs. Learning to fight was really just a front for learning to perfect your character—to feel tired to your bones and persist anyway. There’s a lesson here that transcends fighting — it is the lesson of self-mastery2.

Everything is mental. Your fate itself hinges on the way you see yourself and the world. No skill could be so crucial to your life as mental prowess.

So I ask you to expand your goals. Most people live and die with a handful of goals for their world. Most people solve for a life of full of beautiful things and memories. They try to restructure the world, to influence things, to etch their presence into the memory of future generations. Few people have goals for themselves. I say we should ask more of life.

To latch onto physical goals alone is to grasp life with half your hand. We are capable of far more marvelous things!

If we set goals, they should encompass our whole selves. To borrow from the martial arts, we should train our mind, body, and spirit equally. It is only by rising as a person that you can claim the life you want.

Every facet of your experience, good or bad, is mental. In other words, your experience emerges from you.


It follows that all change must begin with mental change. You can’t strong-arm a difference into your life without first changing your mind.

Do external circumstances matter? Of course. But no circumstance can rob you of the person you are.

We only achieve what we believe is achievable. So I ask you to set higher sights for yourself. Do not aim for what you want. Aim to become the kind of person who gets what they want.

You must train your mind like your life depends on it. Because it does.

Welcome to Re: Life 👋 !

I’m Aaryan — a junior at Stanford diving headfirst into a world of virology, philosophy, and mild sleep deprivation.

You just stumbled into the weird corner of the internet where I chronicle my life. In every post, I share three brief updates, two random lessons, and one idea to reflect on for the week.

Let’s begin.

🎬 Three Brief Updates 🎬

// It’s December now. The frost is settling, and I’m wrapping up Fall quarter at Stanford! It’s always a sprint this time of year, and life is currently a smoothie of calculus, mechanics, and scribbling essays for my modern Japanese literature class.

// As a sequel to my work discovering new viruses, I’m continuing my research at Stanford Medicine. For now, I’m collecting a library of environmental samples around the Bay (think soil, foliage, wastewater, etc.). The goal is to find even more interesting microbes very soon!

This video is from my recent visit to Palo Alto Water Recovery Facility to collect field samples (it was practically empty when I arrived, and with the birds fluttering in silence, it felt like another planet)!


// In the time that’s left, I’m reuniting with old friends, training for an upcoming karate tournament (yes, it was last-minute!), and catching up on the latest Dan Brown novel. All considered, life is good.

🎉 Two Little Lessons 🎉

Year of the Fire Horse
In 1966, Japan’s birth rate fell by nearly 25%. The cause wasn’t sickness or war, but the zodiac calendar.


The Loudest Sound in the World
People could hear it on the other side of the planet.

🧠 One Simple Idea 🧠

Investing legend Charlie Munger on being of service:

The best thing a human can do is to help another human being know more.

Knowledge is free — why not be generous?

Challenge for the week: what can I share with someone I know to make their life brighter?

Best,
Aaryan

Welcome to Re: Life 👋 !

I’m Aaryan — a junior at Stanford diving headfirst into a world of virology, philosophy, and mild sleep deprivation.

You just stumbled into the weird corner of the internet where I chronicle my life. In every post, I share three brief updates, two random lessons, and one idea to reflect on for the week.

Let’s begin.

🎬 Three Brief Updates 🎬

// It’s somehow November and junior year is in full swing! These days, you’ll find me scribbling notes for physics, banging my head on second order differential equations, or catching up on Sōseki’s canon for our Japanese literature class. In other words, business as usual.

// Midterms have been vanquished, and I’m doubling down on my virology research. Right now, I’m investigating how pathogenic Pseudomonas bacteria respond to a dual-barrel attack of phages and antibiotics. (It’s times like these when I wish I could run experiments all day…)

// In the time that’s left, I’m thinking, writing, and finding some peace through long walks around campus. (Nature, I’ve realized, is quite underrated). Of note, I’m reading Black Rain by Masuji Ibuse and recently published a piece on how viruses could control human weight.

🎉 Two Random Lessons 🎉

Oracle Bone Script
What the earliest Chinese characters looked like.

Ozempic Came from a Monster Lizard
How we accidentally discovered the world’s most valuable drug.

🧠 One Simple Idea 🧠

Dostoevsky on the dangers of overthinking.

I swear to you that to think too much is a disease, a real, actual disease.

Introspection alone will paralyze you. Your life begins the moment you change your behavior.

Nothing moves without the courage to try. So try.

Best,
Aaryan

Disclaimer: Phage biology is a rapidly evolving field. All the data and literature I present in this piece are current as of Nov 10, 2025. If you’re reading from the far future, I always recommend reading up on the latest primary research.

Table of Contents

• The Curious Case of the Growing Cows

• Small Cells, Big Weight

• The Silent Sparkplug of Disease

• Phages to Debug the Gut Microbiome

• The Microbial Targets of Obesity

• The Math of Viral Weight Modulation

• A Phage’s Purpose

The Curious Case of the Growing Cows

Most of our planet’s antibiotics don’t end up in humans, but in cows.

In the 1950s, microbiologists converged on a strange finding. When sick cows were fed with the antibiotic aureomycin, it didn’t just clear their infections. It made them….fatter. Soon after, they observed the same effect in healthy dairy cows, with some gaining up to 5% of their bodyweight — or several tens of pounds — in a matter of weeks (Marshall et al., 1957).

The aftermath isn’t hard to imagine. Word spread. Excitement boomed. Ranchers around the world pounced on the idea, and we’ve been fattening cattle with antibiotics ever since.

At least, that’s the story we hear.

What we ignore is the mystery buried in plain sight — one that has tortured scientists for decades. Why do antibiotics make cows fatter at all?

Small Cells, Big Weight

In the realm of microbiology, the connection between weight and the microbiome has been percolating for years.

Metagenomic surveys of lean and obese populations showed directional shifts in microbial composition and diversity (Aoun et al., 2020). With time, we found that specific genera in the gut microbiome could manipulate nutrient absorption, fat storage, insulin sensitivity, and global metabolism (Van Hul et al., 2023). And we showed that perturbing these microbial communities ( i.e. via antibiotics) could reliably affect weight, which could be restored with bacterial re-transplantation (Zhang et al., 2019).

Microbiology offers some insight into our mystery. The weight gain we see in cows is less likely the result of antibiotics, and more likely a symptom of carpet-bombing the microbiome.

While the execution is unfortunate, the results are undeniable. There is a powerful interface between weight and the microbiome. And if we could engineer it— without the collateral damage of antibiotics — we have a straight shot at tuning human weight.

Fortunately, nature is home to a far more elegant solution. Over billions of years, bacteriophages have learned to infect bacteria with freakish precision. Because of this superpower, much of our field has focused on turning phages into antibiotics. Meanwhile, we’re ignoring how the same precision could let phages engineer the human microbiome.

As we continue to reformulate disease through the lens of microbial disarray, phages could be the ultimate tool to restore health through the microbiome. If microbes are as crucial to human physiology as we think, phages could be poised to flip medicine on its head.

We’re approaching a future where every dysfunction in human health could be targeted with phages. And obesity happens to be our most promising target.

The Silent Sparkplug of Disease

Why target obesity, of all conditions?

For one, it’s upstream of almost every disease that matters to us. Cancer. COVID-19. Type 2 Diabetes. Alzheimers. Atherosclerosis. It’s hard to find a single chronic health condition that isn’t driven or worsened by obesity.

This is precisely what makes it important. Obesity is perhaps our closest example of a meta-disease—a single target that lies upstream of almost every single condition that plagues humanity.

It’s well-known that most cases of obesity can be managed with lifestyle. But while lifestyle changes are effective at the individual level, they’re proven to fail at societal scales.

As I write this article, nearly every nation with a GDP per capita ≥$10,000/person/year has an obesity rate above 10% (NCD-RisC, 2024)1. While this is a simplification, the trend is unmistakable. With economic prosperity comes an explosion of processed, calorie-dense food and an increasingly sedentary lifestyle. And the result is unprecedented obesity.

As long as we live in a free and wealthy society, obesity will persist. And no clear-eyed person is suggesting we abandon free and wealthy society.

If we believe that obesity is inevitable, there is only one question that matters. Do we choose to prevent it? Or do we scramble to treat it when it takes hold and shapeshifts into every other disease imaginable?

Because it seems like our current solutions are doing the latter. Today’s methods to manage obesity are remarkably tasteless. Until the release of Wegovy in 2021, our options were limited to dietary changes, bariatric surgery, and a handful of prescription drugs with questionable safety profiles (Sherman et al., 2016).

A glimpse of this data speaks to our reality. Most of these approaches are prohibitively expensive, riddled with off-target effects, and still fail to produce sustainable weight loss. And all of them are reactive patches to obesity.

Meanwhile, obesity has the strongest microbial argument of any disease.

Our first glimpse into the microbe-metabolic axis2 emerged from Fredrik Bäckhed’s landmark studies on microbial transplants. Nearly two decades ago, Bäckhed’s group found that germ-free mice transplanted with microbes from obese donors deposited significantly more fat than recipients from lean donors (Bäckhed et al., 2004).

With time, we solidified this phenomenon from several angles.

Subsequent studies found that the ratios of two gut genera (Firmicutes and Bacteriodes) allowed mice to gain less weight than conventional mice with an identical diet (Murphy et al., 2010). Biochemically, we mapped dozens of microbial pathways that could alter weight—from lipid oxidation to inflammation to hunger signaling (Blaser et al., 2013; Carmody et al., 2023).

The science isn’t controversial anymore: our microbiome plays a key role in tuning our weight. What if we could engineer it?

Phages to Debug the Gut Microbiome

Using antibiotics to tune the microbiome is like knitting a sweater with a baseball bat.

The central bottleneck is precision. Any effect on weight comes at the cost of upending the entire microbiome, often for months (Ramirez et al., 2020). It’s no wonder that cattle raised on subclinical antibiotics develop more opportunistic and drug-resistant infections than almost any other animal (Trevisi et al., 2014).

Phages, on the other hand, are ferociously specific. Since 1950s, we’ve known that phages can distinguish between single-receptor variants of bacteria (Abedon et al., 2010). Pharmacokinetic studies showed that certain phages could be cleared from the body in minutes, meaning their effect on the microbiome is likely transient and reversible (Dąbrowska, 2019).

While these quirks make phages tricky as therapeutics, it makes them perfect to engineer the microbiome.

On paper, phages are the perfect vehicles to modulate human weight. This motivates another question: What’s stopping us?

In practice, it’s not very useful to enumerate the benefits of phages.

If the approach was convincing enough, it would already exist. What’s far more useful is inverting the problem. What are the key technical challenges preventing phages from engineering the microbiome?

If we’re rigorous, we’ll find that our idea assumes the following:

1. Isolate a bacterial strain that consistently and mechanistically drives obesity

2. Discover + engineer phages that specifically lyse this bacteria

3. Efficiently deliver these phages to the gut for transient suppression in vivo
   
   

To paraphrase: we need a sharp weapon, and a reliable target.

Fortunately, we’re not starting from scratch.

It turns out that phages have been formulated as oral therapies for nearly a century, ever since Félix D’Herelle used them to treat the first cases of bacterial dysentery (Summers, 2012). After years of optimization — especially in phage centers like Eliava — we’ve developed a solid foundation of in vivo data, and a significant body of research on enteric phage delivery3.

While these challenges certainly aren’t trivial, I’ve already touched on these in my piece on phage immunogenicity, and covering it any fairness would be another article. As the literature suggests, the packaging of our phages is likely the most stable of our assumptions.

If anything, the largest uncertainty of engineering the microbiome doesn’t lie in our phages, but in our ability to find and engineer bacteria with precision.

Let’s dissect this carefully.

The Microbial Targets of Obesity

Which bacteria has the strongest implication in human obesity?

After careful analysis of the research, I’ve realized that this is an open question.

Longitudinal genomics reveals that the gut microbiome is remarkably plastic — shifting with diet, geography, and environmental stimuli — even within the same individual over time (Xu et al, 2014; Yatsunenko et al., 2012).

It follows how this complicates our solution. Even if we found a bacterial species associated with obesity, it’s a real task to find a baseline level of bacteria associated with sickness or health4.

And even if we could catalog all the bacteria in the gut, they would still be troublesome to study. How can we tell, for instance, if a bacterium drives obesity or simply thrives on a high-sugar diet that drives fat gain?

Testing this involves knocking specific strains of bacteria in and out of the gut, which we can only partially achieve with antibiotics or microbial transplants5. While this doesn’t invalidate our answers, it certainly limits their resolution.

But what does the literature say?

Perhaps our strongest evidence for obesogenic bacteria leads us to a species called R. gnavus. It’s a gram-positive anaerobe thought to modulate weight by extracting calories from glycans that line the intestinal lumen.

Metagenomic surveys show that R. gnavus is a universal resident of the gut microbiome, and has been isolated from humans irrespective of geography, diet, and environment (Nooij et al., 2025). Population-level studies have also reveal a positive relation between R gnavus and obesity, and levels of R gnavus are predictive of weight gain patients receiving fecal microbial transplants (Palmas et al., 2021; Hong et al., 2023).

While this is great, identifying a bacterial culprit feels shallow. If we designed a therapeutic, what phages would we need? How much? How long would the dose last? How would we avoid resistance or downstream effects on microbiome?

Sculpting the gut microbiome isn’t as simple as cherrypicking bacteria and phages. We need to understand the mechanics.

The Math of Viral Weight Modulation

Again, isolating bacterial targets against obesity is no small feat. But for the sake of a model, let’s pretend our target was R. gnavus. How might we use phages to sculpt this bacterial population and control weight?

The first step, of course, is finding a lytic phage that’s active against our target. A quick search on NCBI shows that we’ve already isolated and sequenced at least ten phages against R. gnavus. One workable example is phage RgPS6, which is known to lyse R. gnavus without infecting other bacteria in the same genus6.

After identifying a phage, we can use sequential evolution to optimize its virulence in the gut microenvironment7. We can then propagate the phage to billions of pfu/mL and measure its ability to suppress bacterial growth.

Which leads us to another relevant question—exactly how many phages would we need?

While questions like these can only be resolved experimentally, I decided to crunch the numbers.

Last weekend, I sketched out some differential equations to simulate phage dynamics in the gut. For context, I structured my math on the Levin–Weitz–Beretta regime of viral kinetics, with some fine-tuning to capture imperfect delivery and phage decay in the human gut (Galtier et al., 2016).

For context, B(t) is the population of uninfected R. gnavus population (cells/mL). I(t) is the population of infected R. gnavus cells undergoing lytic replication (cells/mL). P(t) is the concentration of free bacteriophages in the gut lumen (PFU/mL):

After finding some scientifically-grounded values for each of these variables, I modeled the behavior of a one-shot oral phage dose in MATLAB. Specifically, I wanted to solve for how many phages we’d need to kill 50% of R. gnavus in the gut in 24 hours:

This reveals some valuable insights. Even if we were reckless enough to rapidly eliminate half the R. gnavus in our gut, we’d need a one-shot dose of ~6x10¹¹ plaque-forming units. Once again, mathematics can’t substitute for a real experiment — but it does offer an order of magnitude to ground our thinking.

Even if we massively underestimated our phage dose by 100x (i.e. improper delivery, chemical degradation), this figure still falls well within the range of propagation. With some optimization, it’s even plausible to squeeze a working dose of phages into a 1mL, weekly oral pill.

There’s another observation worth noting. Our graph for bacterial load shows that our population of R. gnavus rebounds in a matter of days, as the bacterial community turns over and phages are cleared from the gut. Interestingly, these timescales align with our literature on phage decay in vivo. And it suggests that we could modulate human weight with minimal long-term damage to the microbiome8.

To any phage researchers reading this, it’s obvious that none of these steps are magical. All of these protocols fall within the realm of basic phage biology. These are experiments we can run today. And they are simple enough to produce meaningful answers in a month’s time.

Still, hardly anyone is trying to engineer phages to control weight. For all its potential impact, the concept is seriously overlooked.

In other words, it’s wide open for research.

A Phage’s Purpose

The next few years could be the most exciting season in phage research.

Since the invention of germ theory, bacteria were shackled to the world of infectious disease. Phages were limited to basic science and seen as unwieldy therapeutics.

But the truth is stirring. In recent years, microbes have been reported in every major organ system — manipulating processes in innate immunity, nutrient assimilation, endocrine function, and cell signaling. Diseases that we long assumed to be purely genetic and environmental — cancer, diabetes, Alzheimer’s — are being revisited from a microbial perspective.

Microbiology could be our most flagrant gap in modern medicine. And phages are poised to become the foundation of microbial therapeutics.

We can debate the speed, but the trajectory is inevitable.

Obesity is arguably the largest meta-problem in health, and it could be the most immediate application of phages. In a weight loss market bloated with subpar solutions, phages have all the markings to become a cheaper, safer, sustainable alternative. And developing them is already in the range of today’s microbiology.

This advance alone could make for a life’s work. But it points to something far greater.

As we discover that bacteria run our world, phages are poised to become unfathomably useful. We’re approaching a future where microbes are sculpted in service of humanity. Phages could become the chisel that lets us reshape biology itself. And as phage researchers, we’re in the ideal position to help.

This is the true potential of microbiology — it’s the next logical step in the evolution of phages.

Let’s be remembered as the people who made it happen.

Footnotes

Welcome to Re: Life 👋 !

I’m Aaryan - a rising junior at Stanford diving headfirst into a world of microbiology, hardware, and mild sleep deprivation.

You just stumbled on the weird corner of the internet where I chronicle my life. In every post, I share three quick updates from my life, two links to noodle on, and one idea to reflect on for the week.

Let’s begin.

🎬 Three Speedy Updates 🎬

// The (nonexistent) rumors are true! I’m back in Tokyo, this time through a nearly 70-year-old exchange program between Stanford and Keio University.

Fortunately, I’ve been transplanted from my old studio apartment into a host family and a platoon of Japanese college students. It certainly isn’t biophysics research, but every day feels like it’s been reconfiguring my brain to the language and culture. I’m having a blast!

// Last week alone might have been more eventful than most of my summer.

So far, I’ve: scaled Tokyo tower by foot, received a private tour of the now-decommissioned Fukushima reactor, stargazed with friends from a hotel that was formerly an abandoned elementary school, and (of course) gorged on conveyor belt sushi with my two mischievous host brothers. Stay tuned!

// Still wandering, reflecting, and tinkering on spontaneous ideas. A few weeks ago, I built a genetic engine called PhageBOLT that identifies therapeutic viruses from any sample of DNA. More experiments like these underway!

Strange as it sounds, it doesn’t hurt to see summer setting. So much joy has burst into my life in these past months, and every day reminds me how grateful I am to have seen it.

Whatever the next month brings, let’s crush it together :)

🎉 Two Random Resources 🎉

Human Capital Fellowship
Earn top support $250K in funding for your next big idea, no strings attached. Apply before Oct 19th, 2025.


What’s My Voice Register?
A handy tool to check if you’re a baritone or soprano, and everything in between. Hum into your laptop and see how you fare against other singers!

P.S. If you have a resource for Re: Life — whether you’re hiring, promoting fellowships, or want to share a great read — email me at aaryanh@stanford.edu. You’d be a help to everyone, and I’ll shout you out!

🧠 One Interesting Idea 🧠

Austrian poet Rainer Rilke on the lightness of feeling:

Both pleasure and pain are poison alone. You must learn to sleep on clouds, and you must learn to swallow thorns.

Let your heart fall into everything, and life becomes whole.

Best,
Aaryan

Welcome to Re: Life 👋 !

I’m Aaryan - a rising junior at Stanford diving headfirst into a world of microbiology, hardware, and mild sleep deprivation.

You just stumbled on the weird corner of the internet where I chronicle my life. In every post, I share three quick updates from my life, two links to noodle on, and one idea to reflect on for the week.

Let’s begin.

🎬 Three Speedy Updates 🎬

// For the past month and a half, I was an exchange student at Tokyo University developing wearable optical biosensors.

Notable experiences include: teaching myself electromagnetism in a week, developing early-onset scurvy (why are apples in Tokyo so expensive?!), tinkering with cutting-edge plasma deposition machines, and watching Enoshima’s summer fireworks bloom against the Pacific Ocean. (Now that I think about it, this probably deserves its own post…)

I’m supremely grateful to the UTRIP team, my fellow UTRIP researchers, as well as the Goda Lab and Kitahama team for making this experience possible.

// Every morning in Japan, I would force myself to waddle out of bed and write five haikus. (As you might expect from me by now, there was precisely no reason for this — just another way to spice up life.)

Somewhere in that timeline, I got carried away and ended up with a few hundred poems (!), which I’m now compiling into my second book. I’ll save the details for later, but look forward to it!

// Back home in Canada, I’m currently wading through a deluge of missed emails, wandering town with high-school friends, and writing down my stray thoughts. Returning from Japan feels like someone turned my head upside down — nothing feels obvious anymore and I’m brimming with questions.

I’m restless again, and that’s a good thing.

🎉 Two Random Resources 🎉

The Useless Web
A random wormhole to websites you didn’t need. Extra fun if bored.

The Fall of Sarepta Therapeutics
How three deaths in a gene therapy trial toppled a multibillion-dollar giant.

🧠 One Interesting Idea 🧠

Notes from the Tao Te Ching on communication:

True words aren't eloquent; eloquent words aren't true.

[The wise] don't need to prove their point; [those] who need to prove their point aren't wise.

When in doubt, the best words are often the simplest.

Sharpen your thoughts to their essence, and they become most potent.

Best,
Aaryan

Welcome to Re: Life 👋 !

I’m Aaryan - a rising junior at Stanford diving headfirst into a world of microbiology, hardware, and mild sleep deprivation.

You just stumbled on the weird corner of the internet where I chronicle my life. In every post, I share three quick updates from my life, two links to noodle on, and one idea to reflect on for the week.

Let’s begin.

🎬 Three Speedy Updates 🎬

// After finals week and perhaps the quickest move-out in recorded history (1h 16 mins), I just wrapped up my sophomore year at Stanford. It really is strange, you know — how time slinks away before you can catch your breath. And yet, this year has taught me so much, and it’s hard to find any regrets. Off to the next one!

// I’m in Japan right now! So far, I’ve splitting my time between biosensor research at UTokyo, exploring ancient shrines in the countryside, and repeatedly brushing up on my Japanese after losing my way in the metro. More updates coming soon.

P.S. I love making international friends! If you’re reading this from Tokyo (or somewhere reasonably close), let’s meet up — shoot me a message at aaryanh@stanford.edu and I’ll buy you a coffee!

// Side-quest: A few weeks ago, I decided to teach myself digital photography. So I cancelled my plans and spent the next 24 hours snapping hundreds of photos of bicycles (because why not?). Then I figured out Kindle and published it as a book (this is basically the product of procrastination so message me if you want a free copy).

🎉 Two Random Resources 🎉

Robots Playing Soccer

China just hosted the world’s first 5-on-5 soccer match with humanoid robots. Some were carried away in stretchers.

Virtual Cell Challenge (Arc Institute)
Model how a cell responds to gene perturbations and win $100k (s/o to Daniel Kaminski for relaying this!)

🧠 One Interesting Idea 🧠

Paul Graham (founder of Y-Combinator) on the value of action:

If you can imagine someone surpassing you, you should do it yourself.

Your fiercest thoughts become the axis of your life. There is no one to wait for but yourself.

What fraction of yourself are you holding back right now?

Best,
Aaryan

Welcome to Re: Life 👋 !

I’m Aaryan - currently a sophomore at Stanford diving headfirst into a world of microbiology, hardware, and mild sleep deprivation.

You just stumbled on the weird corner of the internet where I chronicle my life. In every post, I share three quick updates from my life, two links to noodle on, and one idea to reflect on for the week.

Let’s begin.

🎬 Three Speedy Updates 🎬

// Still reading, thinking, and writing about viruses — just published an immersive piece on how we fall short discovering new microbes.

// Continuing research at the Bollyky lab, currently engineering E. coli to express human interleukin 1 (hIL-1), an important immune signaling protein.

// Studying for finals….spending the rest of my time reading Ned Block’s philosophy, learning about marine biology in Monterey, and scribbling essays from coffee shops.

🎉 Two Random Resources 🎉

Hack Club for Builders
Spend 100 hours working on any project, get flown out for an all-expenses paid summer in SF.

Honeybees Engage in Thermal Warfare
One of the most fascinating biological adaptions I’ve ever seen.

🧠 One Interesting Idea 🧠

Friedrich Nietzsche in a private letter to Franz Overbeck:

Nothing helps; I must help myself or I am finished.

You could win every medal and it wouldn’t solve a thing.

What are you seeking from the world? Are you sure it’s not just a sharper version of yourself?

Best,
Aaryan

Disclaimer: Phage biology is a rapidly evolving field. All the data and literature I present in this piece are current as of May 14th, 2025. If you’re reading from the far future, I always recommend checking the latest primary research.

Discovering microbes isn’t some arcane pastime—it’s the heart of microbiology.

Flip through our scientific timeline, and you’ll notice microbes everywhere.

From Iceland to India, yeast have helped humans ferment for thousands of years. Bacteriophages enabled the discovery of CRISPR. Even molds led to the discovery of penicillin, enabling a generation of antibiotics that extended the human lifespan by nearly two decades (Hutchings et al., 2019)

The pattern is strikingly clear. Some of humanity’s most impressive biological triumphs— from vaccines to restriction enzymes—were either enabled by the discovery of a new microbe or inspired by its unique biology.

And yet, as one of the most exciting frontiers in science, microbiology remains shockingly unexplored. In one review, Rappuoli et al. (2023) estimated that our planet harbors at least a trillion unique species of microbes. But scroll through NCBI’s dataset of microbes and you’ll find ~100,000 species — less than .00001% of what exists.

If our scientific empire is built on such a tiny sliver of the microbial world, what possibilities are we missing out on? And more importantly—what’s stopping us from finding more microbes?

As it turns out, there’s a reason for this. It’s less that we don’t want to and more that we’re bottlenecked by our tools.

Today’s methods of isolating microbes are inherently selective. When we hunt for viruses, we select against a host. When we culture bacteria or fungi, we grow them in media that nurture some cells and starve others. If we want to enable the microbial renaissance, we need a truly agnostic test — one that can identify microbes indiscriminately and at scale.

Meanwhile, at the Pasteur Institute, Mart Krupowic’s lab has discovered a novel element in bacterial genomes capable of replicating DNA without primers. While these modules, termed pipolins, have shaken a basic axiom of DNA replication, they’ve largely been sidelined as a scientific curiosity. (After all, why would anyone want a non-specific DNA polymerase?)

And yet, it seems like we’ve overlooked the most interesting application of pipolins — microbial discovery. The same machinery that lets pipolins replicate DNA could enable the world’s first primerless PCR. Effectively, this would let us amplify trace genomes from bacteria, viruses, and parasites — regardless of how little we know of their sequence or structure. It would offer the first complete snapshot of our microbial world.

Our best science has always emerged when a compelling idea finds its proper use. Pipolins are up next.

Hunting for Microbes

There are already many ways to catch microbes in the wild. Most methods either resort to growing microbes from the environment, or directly sequencing their genomes.

However, as I demonstrate in my earlier piece, both systems suffer from the microbial analog of selection bias. Even the simple act of streaking soil samples on a plate filters bacteria—in this case, based on their ability to metabolize nutrients in the media1. Today’s methods of isolating microbes are inherently selective, and therefore exclusive.

On the other hand, techniques like metagenomic sequencing let us probe entire microbial communities, but only when there’s enough genome from each resident. With the current detection thresholds of metagenomic sequencing, we’re likely missing out on trace microbes that make up most of our microbial diversity.

We can amplify microbes with PCR, but only when we have specific primers for their DNA. But this quickly leads to a chicken-and-egg dilemma. To amplify a microbe, we need its sequence. But in order to sequence, the microbe already needs to be amplified.

While techniques like these are handy for isolating microbes with known properties, they’re blind to everything else. But what if we weren’t looking for any microbe in particular? What if we wanted to cast the widest net possible and narrow down later

That would call for a fundamentally different net. And this is what pipolins will let us build.

The Lost World of Pipolins

Long ago, back when biology was buzzing with the discovery of DNA polymerase, biochemist Arthur Kornberg isolated a curious protein called DnaG.

With further experiments, Kornberg showed that DnaG didn’t string together novel DNA, but instead laid down short scaffolds of RNA where DNA polymerase begin replication (Kornberg et al., 1978).

Since then, our knowledge of primers has flourished. In animal cells, primers are built with RNA. In certain viruses, proteins like VpG shoulder this role, latching onto the genome and serving as a foothold for replication to begin.

While the form and process differ, priming itself was always seen as universal. At least, until recently.

In 2017, Mart Krupowic and his group at the Pasteur Institute published a paper that quietly fractured this assumption. While comparing polymerases across microbial clades, the authors identified a novel genetic element. After isolating the resulting enzyme, they found it had the strange ability to replicate unprimed DNA, and decided to call it primer-independent polymerase B (pipolB).

Further exploration revealed this wasn’t a stroke of luck—similar genetic modules were found across the bacterial kingdom, in certain phages, and stowed away in symbiotic organelles like the mitochondria.

To understand this better, I’ll let the authors explain directly:

Collectively, these results indicate that piPolB from E. coli 3-373-03_S1_C2 pipolin is able to initiate and perform DNA replication of circular and linear templates in the absence of pre-existing primers or additional protein factors.

Considering how radical this finding is, it’s a surprise it hasn’t echoed further throughout the scientific community.

When you follow this logic, it opens up an incredible possibility for microbial discovery. With the unique capacity of pipolins to join nucleotides from scratch, we could design a non-specific PCR — one that could amplify all the microbial genomes in a sample. By enabling replication without exact primers, this approach could capture the presence of microbes that otherwise go undetected.

Of course, this makes some major assumptions. Let’s think through them in single file.

Q: But don’t microbiologists already have tools to amplify all the genomes in sample? Isn’t this a relatively common approach?

It is true that certain fields in microbiology (specifically gut microbiology) have methods to replicate genomes from entire microbial communities.

The most common technique, known as whole genome amplification (WGA), relies on massive libraries of random primers in hopes of initiating DNA replication everywhere. It’s the genetic analog of a brute force search.

Mathematically, this doesn’t make much sense. Depending on the genome, primers can range from 18-30 nt. Even assuming the smallest size, a truly comprehensive library would need >60 billion unique primers2. Our largest libraries today range up to 24-mers, meaning we still miss out on microbes since we don’t cover the full space of primers.

Even if it did, combinatoric chemistry is expensive. While WGA excels at one-off tests, it quickly becomes impractical as we scale to thousands of samples — let alone the millions we’ll need to map the planetary microbiome.

This is why pipolins aren’t just a convenience. By doing away with the priciest piece of genome amplification (namely, our giant libraries of primers), pipolins could let us replicate DNA as long as we feed our system with dirt-cheap dNTPs and ATPs. It’s a radically different technique since it can scale to unseen volumes of microbes.

Q: But aren’t most polymerases sequence-specific? Do we have any idea if pipolBs can replicate DNA aside from the sequences they normally act on?'

Fortunately, they do.

In the original paper, Krupovic’s group showed that pipolB could initiate replication across a giant space of sequences — from native DNA in E. coli to fully-synthetic 33-mer strands of deoxythymidine.

To illustrate, here’s another quote from the paper:

Furthermore, replication of homopolymeric DNA substrates suggests that, contrary to canonical DNA primases (Frick and Richardson, 2001; García-Gómez et al., 2013), piPolB DNA-priming capacity does not rely on a specific template sequence.

For now, it seems that if the target molecule is dsDNA and it’s structurally accessible, pipolB can replicate it.

Though it’s tough to prove that pipolB acts on all DNA, it’s reasonable assume that it operates on an incredibly broad sequence space.

While non-selective polymerase would be a bug in any other context, it’s exactly the feature we need for microbial discovery.

Q: Even if we could use pipolins to replicate mixed populations of DNA, could we ever assemble reads from so many unique genomes?

As enzymes, we expect DNA polymerases to function as long as they operate in the proper environment (i.e. pH, temperature, cofactors), and are constantly replenished with nucleotides.

If anything, the limiting factor is our ability to assemble DNA.

Currently, our best algorithms to assemble reads from metagenomic sequencing (i.e. SCAPP, Meta Flye, etc.) still need coverages of at least 20-fold to function properly (Yu et al. 2023).

Consider a lone bacterium. If, as a crude estimate, we assume a genome of 5Mbp, replicating this 20-fold is already a massive feat3. Now consider a complex microbial community with billions of bacteria. At least intuitively, this seems even more challenging.

Physically, there must be some upper bound to how many microbes we can resolve in a community. In any case, if there’s a bottleneck in this process, it likely won’t be the polymerase, but the number of genomes we can fit in solution and assemble successfully4.

From a purely biological perspective, Krupovic’s paper rebuts a core assumption about DNA replication. And yet, a quick search on Google Scholar shows that this paper received only 34 citations. At least for the time being, the community seems to view pipolins as a scientific curiosity.

But rightly so.

Historically, DNA primases have glimmered because of their specificity. When we first unraveled their function, our most earliest and most impactful solutions used it to selectively amplify DNA. Think about approaches like PCR, which let us identify bacteria, viruses based on particular sequences.

It’s quite natural that the idea of primerless replication hasn’t caught on. What use could anyone possibly have for non-specific DNA replication?

In practically every use case, it makes sense to seek out precise sequences of DNA. But microbial discovery could be the most important exception.

In this singular, yet incredibly meaningful edge case, this quirk of pipolins isn’t a bug, but a feature. When we scour the planet for genetic footprints of unknown microbes, we want to amplify everything indiscriminately.

Perhaps no one reading this paper fancies hunting microbes. Pipolins might be exactly what this field was waiting for.

Revamping the Microbial Discovery Pipeline

As I mentioned earlier, microbes today are largely discovered through brute force. We begin by collecting samples from the environment, isolate microbes using mostly arbitrary selection filters, then sequence our results. While this approach is routinized and reliably churns out new species, fundamentally wrong. What we isolate simply isn’t representative of the world.

Because of their inherent design, we aren’t seeing all microbes in the planet — merely the small fraction that are responsive to our tests.

If we want to resolve the microbial world (and maintain our sanity) we can’t use a piecemeal approach. We need an agnostic system that can identify all microbes in a sample.

It wouldn’t take much to integrate pipolins into microbial discovery. Here’s one protocol I designed from my work isolating viruses.

Consider a soil sample. After suspending the sample in an arbitrary buffer (i.e. SM, PBS, etc.) and filtering through a 0.2 micron membrane, we’ll have a solution packed with viral particles and small molecules. Treating this with a lysis buffer will give us a batch of exposed DNA.

Alternatively, if we wanted to resolve RNA (as is often the case with animal viruses), we would simply use RT to turn the entire sample into DNA first. Then, much like PCR, we would heat the sample to de-anneal DNA and treat it with pipolB to begin the replication process.

Since pipolins are distinct from normal polymerases, they have unique enzymatic needs. While current literature suggests that pipolB functions optimally with manganese (Mn2+), these parameters can always be optimized with concentration testing.

From here, we would follow the standard PCR heating cycle to amplify all the genomes in our sample.

Then, after sequencing with standard techniques (i.e. Illumina, PacBio), we could then resolve our assembled reads.

As you can see, the bulk of the process remains the same. The end result is still snapshot of a microbial community— the only difference is that we now have a panoramic view.

And Now, Your Turn

As a virus hunter, I believe that microbial exploration is one most important scientific pursuits.

If you’re reading this article, assume you care about this, too.

Microbiology has already changed our world. Now we’re nearing a precipice where microbiology becomes our world and makes it larger.

The community of microbiologists is still small, and that gives us the chance to build the tools that will define this field for generations.

Over the next few weeks, I’ll be in touch with the Krupowic lab to see how our ideas can intersect, and potentially running experiments with pipolins on phage DNA.

This article is an open invitation. If you want to help design and test this approach, write to me and we can find ways to collaborate.

Let’s make this real.

Footnotes

Note: This summer, I’ll be at Tokyo University researching biosensors at the Goda Lab.

Currently brewing up plans to host another Re: Life meetup in Tokyo — shoot me a message if you’re in the area and are interested in joining us!

Welcome to Re: Life 👋 !

I’m Aaryan - currently a sophomore at Stanford diving headfirst into a world of microbiology, hardware, and mild sleep deprivation.

You just stumbled on the weird corner of the internet where I chronicle my life. In every post, I share three quick updates from my life, two links to noodle on, and one idea to reflect on for the week.

Let’s begin.

🎬 Three Speedy Updates 🎬

// Published more writing, including several reflections on Substack and a piece on why we can’t figure out how to count viruses. More work is on its way.

// Wrapped up spring break and starting a new quarter at Stanford. Currently taking organic chemistry, vector calculus, and Chinese buddhist painting (because science without art is lonely!)

// Exploring random buildings in Engineering Quad, practicing karate more seriously, and walking around Palo Alto with my dorm mates!

🎉 Two Random Resources 🎉

Thiel Fellowship
$100,000 for young people working on ambitious ideas.

The Ninth Wave
No one painted the ocean like Ivan Aivazovsky. If you’ve never seen his work, you’re missing something important.

🧠 One Interesting Idea 🧠

Japanese author Haruki Murakami on the volatility of life:

Life is not like water. Things in life don’t necessarily flow over the shortest possible route.

Is all your effort failing? Or are you simply not giving your actions enough time to work their magic?

Best,
Aaryan