Michał Nowakiewicz

For The Love of Food

• 1. This presentation contains forward-looking statements based on animal investigations THE DIVE LAB The Dive Lab  Sydney, Australia  info@thedivelab.com 4 Billion Years of Real-World-Transformative Bio-Logic Innovation.
• 2. HiberNaut Rising of a Leviathan & Healthcare `Magic-Bullet´
• 3. Welcome to the 21st Century, Biology’s Century “Every now & then, rarely really, a technology suddenly & unexpectedly appears from out of left-field & leaves us wonder-struck & enchanted, because it transform the very fabric of our reality. Ideally, such technologies are simple, yet all the while endowed with futuristic-like sophistication & englightment. Preferably, they are deeply human-connected, transcending time, place & occasion. They may even seem invisible & unintelligible, but like the air we breathe & the water we drink, they may be vital, perhaps even a life-force, a quintessence.”
• 4. The (Global) Healthcare Crisis Aging & growing population, greater risk of pandemics, a growing & ill-affordable system. In short, an intractable Gordian-knot standing at 18% of US GDP & rising faster than GDP, i.e., the makings of a perfect-storm.
• 5. Underlying Problem: Broken & Irrational R&D Model The (unsustainable) cost of developing one medicine for just one condition stands at a staggering $4-12B. The reason: less than a 0.02% success rate; not withstanding possibly hidden &/or long-term adverse side effects.
• 6. “We really understand very little of human physiology. We don’t know how the machine works, so it’s no surprise that when it’s broken, we don’t know how to fix it… I don’t have a clue. I have no idea & nobody else does either… The fact that we ever make a drug that gives favorable effects is a bloody miracle because it’s very difficult to understand what went wrong.” - Dr. R. Perlmutter, MD, Merck, 2013 “Doctors are men who prescribe medicines of which they know little, to cure diseases of which they know less, in human beings of whom they know nothing. Then they argue about it, while nature acts & cures the disease [, i.e., where nature has tinkered].” - Voltaire, 1760/Taleb, 2012
• 7. Fragility Unpredictability Change Chaos Randomness Variability Innovation & Business Problem: Red-Queen Effect In the face of a future undergoing accelerated change & competition, solutions without multiple& broad target options makes for risky & irrational positioning. “It’ll take [far more than] all the running you can do, to keep in the same place.” – L. Caroll, Alice’s Adventures in Wonderland Risk Errors Obselescence Disorder Uncertainty Complexity Threat Volatility Noise Unknowns Difficulty Insecurity Confusion Instability Out-/Loss-of-Control Discomfort Danger Fads Adapt Overwhelmed Overcrowded Competitition Fragmentation InnovateEvolve Stress Breakdowns Distress
• 8. The Elusive `Magic-Bullet´ If a solution to all this was ever to be found, it would have to strike at the heart of these problems & with one simple, bold, decisive blow, & out from left-field: • (Almost) one-stop-shop all-purpose • Democratized • Decentralized • Affordible • Accessible • Preventative • 100% Personalized • Simple • Sophisticated • Fully integrated • Fast • Safe Does such a brushstroke solution even remotely exist?
• 9. Maybe you didn’t know it, but since at least the 50s, establishment-heavies have spent over $100m-BIG trying to crack the code to a `magic-bullet,´ i.e., it exists!
• 10. Believe it, or not, there exists in nature an omnipotent biomedicine, one that’s possibly as old as life itself. “The most amazing metabolic feat in the animal kingdom.” - Prof. R. Nelson, MD, Uni. Illinois It actually seems to be life’s back-up support-system. And, here’s the very cool thing: “It’s latent. The [genetic] hardware exists in humans.” - Prof. S. Martin, Uni. Colorado
• 11. This basic task of this phenomenal marvel is to brushstroke-deal with the threat of metabolic hard times, whatever they may be; it can also do several other things of which I wont go into here. It’s so omnipotent, it possese a completely unmatched capability to, no-bull, deal with: • Obesity • Starvation & hunger • Dehydration & thirst • Trauma • Illness • Disease • Infection • Hypoxia • Poisoning • Darkness & irradiation • Excessive cold & heat • Pre-mature aging & death
• 12. It acheives this by activating the most protective & most mysterious region of the metabolic spectrum, the extreme & supposedly `forbidden´ slow-end. By running the furnace of metabolism down to a cold flame & kind of off-line/default-mode for some time, the biomolecular `magically´ turns on. But, don’t ask how, hence why it’s an enigma! Still, the big take home message is, taking away rather than adding is key, i.e., a less is more approach; Taleb was right.
• 13. “So, just turn the darn thing on,” I hear you say. Well, you see, that’s been the problem all along. “ The trick is knowing how to turn it on.” - Prof. S. Martin, Uni. Colorado Until now, no one has cracked the code to this most elusive & enigmatic biomedical marvel. Secondly, it’s all been blue-skies discovery science, & only a very few in the medical establishment knowing either of its awesome potential. Indeed, it’s defied understanding for over 200-years, too the extent that it reads like a hunt for some long-lost, mythical treasure. The stuffof sci-fi & Hollywood!
• 14. If you haven’t figure it out by now, I’ll just say it .... human hibernation!
• 15. It’s not sci-fi, but let me quickly ramp-up the ....
• 16. The very `cool´ features.
• 17. It’s a metabolic state that’s widespread & common in nature. In one form or an other it’s found in all lineages. If one knows what to look for, one can see it everywhere.
• 18. Common & widespread in mammals too, but somewhat difficult to observe & study because it occurs in silence, out-of-the-way, often hidden & under the cover of darkness.
• 19. Even primates express it. Some do it daily, others seasonally, & in tropical jungles! Some even bury themselves alive under a foot of dirt! We’re talking a full-blown metabolic shut-down for 7 months straight, i.e., default-mode of existence, plus no eating, no drinking & `lights-out.´
• 20. Of course, anecdotes of human survival against all odds & a suggestion of a human capability are age-old. Not surprisingly, every time we hear of a possible case we are always unprepared, & so it’s always poorly documented. But, here’s a less than accidental anecdote from back in the days …. “It is an established custom that amongst Yogis (Fakeers) that, when malady overpowers them, they bury themselves.” - Muhsin Fani, ca. 1655, The Dabestān-e Mazāheb, p.138
• 21. Here’s something a little more concrete. Scientific studies from the 30s & 50s unequivocally confirmed a nocturnal capability in Australian desert aborigines, which, by the way, manifested in the same manner as in marsupials sharing this metabolically hostile environment. Unfortunately, the key was lost, as no one then realized the opportunity. “Although their body temperatures were low, whilst asleep, or when just awakened, they did not shiver or show signs of being cold or in discomfort. They were, in fact, torpid.” - Prof. C. Stanton-Hicks, 1933, Adelaide University
• 22. Hibernation is a complete rule-breaker because it permits metabolic-rate to drop well below a purportedly basal rate; some 70-90% below sleep rates in a human- sized animal. In other words, you would consume so little oxygen & tolerate hypoxia sowell you could hold your breath for a very, very long time! Universal Minimum Basal Metabolic Rate(BMR) Human/Black Bear - Infant/Cub 10kg - Adult 70 kg Little scope for reduction in metabolic rate &, hence, cooling Lots of scope for reduction in metabolic rate &, hence, cooling
• 23. When I said, it exists everywhere, I meant it, but one has to perspective-shift somewhat because it can be completely invisible. The fetus, submerged, has a lower metabolic-rate than what physiologic law dictates for a comparable sized animal; it’s the same as it’s much larger mother. One could say, it’s in a relative state of hibernation! And, even after birth, the metabolic furnace takes several days to fully crank-up.
• 24. Hibernation, torpor, call it what you will, goes by many names & comes in many shades, depending on the trigger, the critter, the degree of metabolic suppression, duration, & even type of activity! One can think of hibernation as a deep & protracted form of torpor. Lying-down Standing Walking Diving
• 25. Because it conserves energy, vital-signs are much suppressed, sometimes plummeting to off the chart. Body-temperature drops, including that of the brain; heart-rate may fall to single-digit values; breathing slows to a small fraction of normal rates; &, blood-flow pitters-out to a slow trickle, preferentially redistributing to more vital organs.
• 26. On a cold flame, most biomolecular pathways, like, DNA synthesis, cell-division, etc., slow-down to a near-stand- still. Kind of makes one think that one wouldn’t need much of a hair-cut or shave as things simply wouldn’t grow very fast! Though the biologic-clock slows down, BIG time, & many pathways go into a sort of metabolic holding-pattern, some things are, paradoxically, much up-regulated to confer enhanced protection, promote bodily-repairs & even regeneration.
• 27. Brain cells shrink (!), & interconnections much withdraw, all to further conserve energy & better tolerate metabolic stress. Organs undergo notable morphologic changes. By all accounts, the brain resembles a forest in the winter: cold, leafless & with the branches pruned back, i.e., until reboot, at which time it all promptly comes back online & to full-bloom, & at unbelievable rates. Active neuron Hibernating neuron
• 28. A buckle-down, `lights out´ & wait-it-out approach is sometimes the best medicine for coping with hard times. But, don’t be fooled by the oblivious & slumbering comfort, it isn’t really sleep, & at low temperatures there’s little to no brain-wave activity, hence, probably neither dreaming or memory; actually quiet an advantage, otherwise one would become awfully frustrated & probably very depressed lying there months on end.
• 29. THE BIG DEAL Based on the extensive critter observations, there’s every reason to think that a human-enabling capability would similarly offer us with access to Pandora’s box of phenomenal biomedical marvels, one’s that go far beyond providing Ken & Barbie with a means to go on a SpaceX adventure to back-up humanity out there, somehwere. Based on critters, here’s to looking over the horizon
• 30. Famine + Hibernation “The most effective energy-conserving strategy available to mammals. Substantially reduces resource requirements, minimizes the risk of starvation, thirst, & extinction.” - Prof. F. Geiser, Uni. of New England
• 31. OBESITY EPIDEMIC PANDEMIC An intractable problem of gargantuan proportions: • 1 in 3 obese, heading to 2 in 3 • Directly & indirectly `consuming´ as much as 20% of the US annual healthcare budget, or $200B!
• 32. “Reversing obesity is not going to be done successfully with individual effort. I don't think we’re going to treat our way out of this epidemic with pills or surgery. We need to redesign the environment.” - T. Frieden, MD, Director, CDC “The current quest to develop a single anti-obesity drug, or a small is misguided, because there are too many potential problems to be targeted by a single drug, or indeed any small number of drugs. We can see that there are many, many different ways in which the system can go wrong, with more variety than commonality; a very unwelcome fact for most people.” - Prof. A. Jenkins, Garvan Institute
• 33. “The switch-over of metabolism, to use fat instead of carbohydrates as primary fuel for the body, is the main task of hibernators.” - Prof. M. Andrews, Uni. Minnesota
• 34. If we can’t stop or reverse the crisis, & since we’ve a `fat´ chance of redesigning the environment, maybe we should leverage it! Obesity + Hibernation = Fat Muscle Loss  Starvation
• 35. Medical Emergencies + Hibernation
• 36. Infections + Hibernation Disables &/or kills pathogens by suppressing pathogen metabolism, indirectly via host, &/or ! • Viruses • Some parasites • Some bacteria
• 37. Cancer + Hibernation • Cancer ceases to grow & spread, may possibly even be prevented from ever developing; is possibly even killed, i.e., implying more time to intervene • Chemo- & radio-therapy are better tolerated, resulting in fewer & less severe side-effects, &, potentially, broadening the patient inclusion criteria.
• 38. Organ Transplant + Hibernation Increased organ viability & immunosuppression, potentially resulting in decreased organ rejection & reduced reliance on `half-baked´ immunosuppressive therapies, with all their adverse side-effects.
• 39. Nervous System Damage + Hibernation The spinal cord can amazingly repair itself & even regenerate. So too, the retina, the muscles, all can re-innervate themselves. The possibilities are simply way too fantastic to contemplate.
• 40. Neurodegenerative Disease + Hibernation Reduces neuro-inflammation, the incidence of seizures. Question: If it also repairs the nervous system, one can’t but entertain the thought of, what of neurodegenerative diseases?
• 41. Bioinformatics & Diagnostics + Hibernation Suppressed metabolism suppresses a (noisy) background of metabolic pathways, thereby potentially generating more informative, relevant, specific, & sensitive biomarkers of health, disease, & drug-action.
• 42. Drugs + Hibernation • Reduce reliance on prescription medications. • Potential for more specific targeting with reduced adverse side-effects
• 43. All that was just the tip of the iceberg! Hunger & Obesity Thirst Infection Cancer Trauma Stroke Neurodegeneration
• 44. Sports & Fitness Endurance Performance + Core-Body Cooling
• 45. Aging, Youthfulness Aging-Related Diseases, & Longevity + Hibernation The final frontier & the no. 1 time-risk-factor to just about everything! “Aging & aging-related diseases are our greatest medical & societal challenges.” - Dr. C. Venter, Human Longevity Inc.
• 46. As telomeres degrade, the DNA within chromosomes begins to unravel, & cell-replication ceases. On cue, aging & the incidence of aging-related diseases fast-track.
• 47. But, add hibernation to the mix: • Maintains, repairs, & regenerates telomeres (stem cells & progenitor cells!?) • Reduces risk of aging-related diseases • Promotes youthfull behavior & appearance • Slows the biologic clock (aging) with minimal loss of (active) life-time credits • Increases life-span
• 48. Global Energy & Pollution + Hibernation Consuming, demanding, wasting & polluting less, & more slowly: • Food • Water • Fossil fuels • Emissions
• 49. A platform-means to fast-track other as yet unrealized & unimagined great discoveries.
• 50. Augmented reality: Mars, infinity, & beyond!
• 51. 100,000 ft View Doing more good than could possibly be imagined or captured: • Virtual overnight save of hundreds of millions of lives & avoidance of imeasurable suffering • Saving of hundreds of billions, if not trillions of unaffordable global healthcare dollars • Empowering all
• 52. The Hack.
• 53. Now, I’m a Curious-George & a bit of a wonder-junkie. I also happen to hang-out far to left-field, on the wild-side of life & the intersection of virging scientific-fields. There, serendipity & innovation proliferate; almost anything goes; old ideas collide; perspectives get 180-degrees shifted; new ideas are born; profound truths are revealed; &, age-old dogmas debunked. From such a perspective, it seems, to me, that the enigma of hibernation has been an elusive & formidable challenge specifically because we seem to have lost touch with reality, creating convenient, albeit artificial truths, ones that have then blinded us from the very things we seek.
• 54. About a dozen years ago, I hatched a bold & audacious plan to crack the code to this most puzzling & elusive enigma. But, I wasn’t planning on doing this by sifting through mountains of complicated, interconnected & fickle molecular pathways, & then create some exotic cocktail. Rather, I planned to unlock & then enable it.
• 55. Of course, to many, human hibernation will always sound like sci-fi, an outright impossible metabolic feat say, forbidden metabolic territory reserved only for critters. Others, no less, see it as some sort of unintelligible & super-complicated `rocket-science,´ something perhaps only to be realized in the far-distant future.
• 56. Indeed, despite an extensive world-wide search, no switch nor trigger has ever been found, in any critter, let alone any human.
• 57. Considering the many formidable challenges, the Hollywood sci-fi, the hubris, & the fact that such a moon-shot would effectively require debunking several age-old & steadfast `laws´ of physiology & medicine, it quickly became apparent that any cut-the-chase attempts would require jumping off the grid.
• 58. A central cornerstone of physiology & medicine is that, a (healthy) human core-body temperature lies ....  37C Yet, this has never been truly tested. No one has really tried hard to check to see if it’s always the case. Indeed, we’ve simply taken it for granted. But is that really the reality?* * Circadian-rhythms , & fasting, can down-regulate temperature, but these result in only minor temperature decreases (< ca. 1C) & take at least a half-day or more to express. Further decreases, due to overwhelming cold, hypothermia result in increases in metabolic rate in attempt to stay warm, but inevitably the system fails, resulting in irreversible & life-threatening risks in the absence of external re-warming assistance. Likewise, its clinical counterpart, therapeutic hypothermia, despite offering some neuroprotective benefits, results in undifferentiated cooling of all body process once shivering is suppressed, & pathologic side-effects especially if deep & prolonged.
• 59. The fundamental requirement for challenging a human to express full-blown hibernation would be the following: + a classic constellation of additional hallmarks: • From within (autogenous) cooling • (Suppressed) off-the-chart vitals • Sustainable • Promptly reversible • No adverse side-effects • Near-100% fat-burning
• 60. The problem: how to show, for starters any such inkling of a potential?
• 61. Perspective-Shifting “The same advantage which diving mammals find in a reduced heart-rate [& recently discovered core-body- cooling] may be applicable to the bear in winter sleep. It’s possible that the bear may `dive´ into hibernation in the winter, making itself into a heart-lung-brain preparation.” - Prof. E. Folk, 1972, Uni. Iowa “I’m convinced there’s some kind of connection between hibernators & people who’ve cheated death after being submerged in icy water, or buried in snow, without oxygen.” - Prof. M. Andrews, 2013, Uni. Minnesota
• 62. The Missing Link: The Badjao Way out to left-field, away from everyone & everything exist a people largely unnoticed, but with a hidden secret so big it could change the face of modern medicine. They exhale, sink & take a long pause between breaths. They have, in fact, entered into an ultra-rapid state of torpor.
• 63. Dive depths: 15 m Ultra-Rapid Metabolic Shut-Down PS: hacker = guinea-pig Full-lung dives `Empty-lung´ dives Heart-rate is inversely related to metabolic rate
• 64. Temp(C) Time (min.) Debunking the 37C Dogma • Brain-cooling of 2.6  0.3C in 2 min! Or, 15-20% reduction in metabolic-rate (6-8%/C of cooling) • 3x faster cooling than any animal & faster than any medical technology • Independent CRO verified MRI thermometry Hacker
• 65. • Meets all, not just some, criteria for a definition of torpor • Statistically significant & empowered (N = 4 `guinea- pigs + one hacker). Average cooling-rate 1.0  0.3C/min • No `ice-cubes,´ no drugs • Conference abstract presented & available on request • Manuscript in preparation
• 66. There Was Just One Tiny Little Bitty Problem Though this finding shatters multiple dogmas of physiology & medicine, & though this is a newly discovered torpid state in humans, & though it clearly shows that we are, in fact, hidden masters of the torpid `art,´ alas this variant is unsustainable. Still, a good indicator of a potential.
• 67. By the way, it also means that torpor, at least in this form, is hard-wired into all vertebrates &, in one form or another, possibly all life as most certainly, it wouldn’t have survive long without it. Ancient Conserved
• 68. So, back to the drawing-board, another 1,000 all-nighter, more perspective-shifting &, literally, a world-wide clue-hunting expedition to ID a sustainable variant.
• 69. After several years of looking her, looking there, it was all starting to look like I might well be on some wild-goose chase & a long stroll down the path of false hope & empty promises.
• 70. I’d tried everything under the sun & asked everyone. The response was always the same: “Sorry, can’t help you, I don’t even know myself. Looking at me wont help much, that clear. Maybe you just need to try it.”
• 71. And so, on one cold & dark Swedish winter’s night, literally at a last-minute make or get out moment, I decided to go all in, & swing for the fences.
• 72. And, as the `lights´ dimmed, nature revealed one of her longest standing & best kept little secrets.
• 73. The Tipping-Point N=1, first-in-human, sustainable torpid state: all the classic hallmarks & the smoking-gun for a non-negotiable right-of-passage for a human-enabling capability. PS: hacker = guinea-pig 3.5C or 20-30% MR decrease in 12 min. Stopped
• 74. So it’s clear, sci-fi has crossed over into reality .... again! “I fully support your view that you detected a handle for torpor induction in humans. There’s no real reason to say that humans are so different from other mammals that they’re unable to enter hibernation.” - Prof. G. Heldmaier, Philipps-Marburg Uni. “I stand ready to do molecular aspects of the phenomenon.” - Prof. K. Storey, Carleton Uni.
• 75. So, what’s the `trick´ I hear you say?
• 76. The `Coolest´ Ever Human X-Periment First, we’ve got to run the all-hooked-up & no-holds-barred `killer x-periment,´ i.e., the one involving a launch into deep inner-space. Specifically, we’ve yet to find-out just how low a pilot-light she’ll wind-down to & for how long, i.e., before she eventually fires back up the furnace. And, critically, we have to make sure it’s safe.
• 77. I’d also be keen to test her metal by stress-testing her to see how she responds, like with diabolical 1830s-type experiment.
• 78. When I say, “all-hooked-up,” I mean lots of high precision & sensitive gadgets to accurately measure & synchronize all those off-the-chart vitals, things like, e.g., ECG, EEG, O2-consumption rate, fat-burning ability, maybe even some thermal imaging, etc.
• 79. So, understandably, for now, mum’s the word, but truly, I really can’t wait to tell you!
• 80. However, fro now, I can tell you that it doesn’t involve this. I also took the buried alive & submerged bits out of the equation.
• 81. And, the `cool´ thing, you wont have to move to Alaska. You’ll be able to get some deep R&R staying within the comfort of your own home or maybe going to some clinic down Mexico way!
• 82. Seriously: The Technical Risks This is nature we’re talking about & she can be unpredictable at the best of times. We cannot be 100% certain she’ll play ball every time. She may not sustain for very long, nor reach the deep metabolic region required for manifesting some of those omnipotent benefits. Indeed, she may not even manifest any of them. Worse yet, it may be something else altogether, but I don’t think so after quite a few runs). Most certainly, however, if we don’t try, we’ll probably have to wait another 200 yars at this rate, & I ain’t waiting!
• 83. PS: I should probably mention that, when earlier I said, “I hang-out on the wild-side of life,” I mean, I’m an old-school type who specialize in running real-world, cut-the-bull, cut-the-chase `killer experiments,´ to the extremes of life. “A very laudable approach that should [perhaps not] be encouraged.” - Dr. P. Stern, MD, Senior Editor, Science
• 84. HIBERNAUT HUMAN 2.0 Stay tuned for augmented reality!
• 85. THE DIVE LAB4 Billion Years of Real-World-Transformative Bio-Logic Innovation. The Dive Lab  Sydney, Australia  info@thedivelab.com