More companies are investing in renewable energy to power their operations and offset their carbon emissions...Getty Images
EBay at its very core pioneered the circular economy — of finding new homes for treasures that might otherwise have ended up at the dump. “Avoiding items going into a landfill is very important to our customers,” says Steve Priest, CFO of eBay. “Driving the circular economy is part of everything we do.” But finding new shelves for Beanie Babies is just a small component in eBay’s sustainability efforts, which prioritize slashing greenhouse gas emissions.
In eBay’s case, these are mostly tied to electricity used to power vast data centers. Since 2017 eBay has cut its carbon emissions by 29% to 88,000 tons per year. The e-commerce giant became carbon neutral this year, and is aiming to achieve a 100% renewable electricity supply for all its offices and data centers by 2025.
This goal might actually be attainable in the next few years as eBay’s biggest clean energy projects yet come online. The White Mesa Wind Project in Texas (a joint venture with Apple, Sprint and Samsung) began operating this year, producing 75 peak megawatts for the four companies, enough to power 20,000 homes.
Meanwhile the Ventress Solar Project in Louisiana, a virtual purchase power agreement between eBay, McDonalds and BP’s Lightsource division, will generate 345 MW. “We collaborate with our tech peers when some sustainability issues come up, where banding together makes more sense,” says eBay’s chief sustainability officer Renee Morin.
Such efforts have earned eBay the no. 11 spot on our inaugural Forbes Green Growth 50 list. Using emissions data from Sustainalytics and financial data from FactSet Research Systems, we honed in on U.S. companies with market caps greater than $5 billion, that started with more than 100,000 tons of carbon dioxide equivalent emissions in 2017, and have since successfully reduced their emissions while simultaneously growing profitability (as measured by an absolute increase in net income or operating income from 2017-2020).
Going in, we figured these criteria would produce a list of more than 100 companies. But green growth is harder than it looks — both Weyerhaeuser and Edison International, ranking no. 21 and no. 10 on our list, grew earnings less than 2% since 2017.
Is there a connection between cutting carbon emissions and boosting earnings? eBay’s Priest thinks we’ve reached the point where companies that don’t care about green will find it nearly impossible to deliver growth. “Customers want to be associated with corporations that take their environmental responsibilities very seriously. Those that do will continue to drive loyalty from their customer base.”
This is a strategic emphasis echoed by Stephan Tanda, CEO of Aptar, which took the no. 1 spot on the Green Growth 50. Aptar makes myriad drug delivery systems and dispensing products for consumer goods, especially foods and cosmetics. “We look at everything we do through a sustainability lens.” Most of Aptar’s facilities in Europe are already certified landfill free. By the end of the year Aptar is looking to achieve “80% disposal avoidance.”
It’s a business that involves reconciling contradictions — most of their products are plastic, which he says actually has a pretty low carbon footprint relative to alternative containers. A new Aptar product is a “monomaterial” lotion pump with no metal parts, entirely recyclable.
Consumer demand for such new products is arguably more impactful than the kind of government policy circus on display at the recent COP26 meetings in Glasgow, Scotland.
“Governments don’t impact what we do that much. Consumers and patients and customers demand what we do,” says Tanda. They will pay for the carbon transition because it is what they want. Listening to the consumers is how Tanda aims to “future proof our business.”
That approach has worked for electricity giant AES, which landed no. 15 on the Green Growth 50 list after reducing emissions by 22%, replacing coal-fired power plants with wind, solar and batteries — “a winning combination that can decarbonize 90% of the grid,” says Chris Shelton, president of AES Next. Because the costs of renewables kept going down, they were able to shift customers over under a “green, blend and extend” program.
AES also operates a kind of inhouse venture capital operation. Its Fluence utility-scale battery joint venture with Siemens recently went public and now sports a $6 billion market cap — the company behind some of the biggest battery installations in the world.
There used to be a large group of companies “in denial” about mitigating greenhouse gas emissions. “That group is vanishing fast,” with companies moving over to the “bargaining” group, where they want to know the minimum they have to do to get by and keep activists off their back — that’s the insight of Chris Romer, cofounder of Project Canary, which installs laser-based sensors at industrial sites to monitor methane leakages.
The landmark ESG moment, he says, was last year’s ExxonMobil annual meeting, where shareholders voted in more green-friendly board members. There’s no going back. Romer says manufacturers can already earn multiples of their monitoring and certification costs by selling “green” products at a premium.
Even on the Green Growth 50, some companies are less enthusiastic than others. Nicotine giant Altria for example, positioned at no. 35 on our list, seems to be doing just enough, having cut emissions by 10% in the studied time period. But according to its most recent sustainability report, Altria’s renewable energy use is just 2.3% of its total, a surprisingly meager ratio.
Altria also demonstrates how hard it can be to stick to a well intentioned program. The company was making great strides toward reducing the amount of waste it was sending to the landfill. In 2018 it nearly hit its 21 million pounds goal. But 2019 wrecked the trend, when Altria delivered 87 million tons to landfill — mostly rubble from a headquarters renovation. Their next challenge: reducing litter from cigarette butts.
Stronger performers included Eli Lilly, which ranked eighth on our list after the pharmaceutical company swapped out old light bulbs for LEDs at three plants, saving 330 mwh per year. And Bristol Myers Squibb, which heats its Munich, Germany office building with 100% geothermal energy, found itself at no. 13. Church & Dwight, parent company of Arm & Hammer, has meanwhile placed third on the list, having achieved its goals of no more PVC in packaging, and offsets carbon emissions by planting millions of trees in the Mississippi River Valley.
Recently, one of my friends messaged frantically, asking if I had seen the big serotonin study that had been published by scientists at University College London. The study, an umbrella review critically evaluating pre-existing research, concluded that there was little support for the idea that depression was related to abnormally low levels of serotonin. As a philosopher of medicine and psychiatry, I had to confess that I had seen the study and was utterly unsurprised at the results.
It’s true that the authors of the study are controversial figures, vocal to sometimes vituperative critics of the mental health status quo, leaving heated debates in their wake with each new publication. But the authors’ conclusion has been an open secret within mental health circles for at least a decade. The very public dispelling of this “serotonin model” has also removed a key plank in the widely believed but oversimplified myth of mental illness being caused by a “chemical imbalance.” My friend was devastated.
The chemical imbalance myth has its roots in the late ’70s and ’80s when psychiatry was dominated by the desire to understand mental illness in primarily biological terms—as deviations in brain structure, neurochemistry, and genetics. When the first generation of selective serotonin reuptake inhibitors (or SSRI) antidepressants such as Prozac was introduced in the late ’70s, a key part of their marketing claimed that they targeted specific neurochemical imbalances.
Psychiatry is now interested in a wider range of factors contributing to mental illness—including genetics, gut microbiome, environmental influences, socioeconomic factors, and interpersonal stressors—and the marketing of psychiatric drugs is more tightly regulated.
The vast majority of these prescriptions, including the one taken by my friend, are for SSRIs. And it’s no surprise that many people who have been prescribed an SSRI believe that they work by increasing the availability of serotonin, thereby correcting the abnormally low levels of serotonin responsible for her depression. Finding out that this story of how SSRIs work was unsubstantiated made her question whether she should be taking them in the first place.
This is a common reaction. As I write this, my social media channels are full of patients who say they now want to stop taking SSRIs. The response by concerned mental health professionals and skeptical commentators has been twofold: First, they are poking holes in the study—usually an important part of scientific method. But in this case I suspect it is sort of pointless, given that many experts already thought the serotonin model to be a nonstarter, and this is a review of existing work rather than new research. Second, they are correctly noting that though we are unsure how SSRIs and other psychiatric drugs work, we have reason to believe that they do—an important distinction.
Medical treatments, including psychiatric drugs, are primarily tested for efficacy, usually via randomized controlled trials rather than more primary research into how or why they work. In many ways, this makes sense: When there is a problem, especially with one’s health, the priority is fixing the problem rather than working out why this particular fix works. Indeed, there are many common medicines and treatments where we are not entirely sure how they work, despite being fairly certain that they do—including acetaminophen (or, as we call it in the U.K., paracetamol).
In many ways my friend and I are very similar: prone to severe depression, from the same ethnic background, of similar ages, both philosophers. We have both spent the vast majority of our adult lives in precarious environments that incentivized a certain kind of relentless pursuit of achievements. But unlike my friend, I made the choice, not just once but at many critical junctures in my life, not to take antidepressants. Because I knew that depression doesn’t necessarily come from a chemical imbalance, I knew that SSRIs would hardly be a silver bullet or the only thing that would help.
I also thought about what side effects they would have. One of the primary reasons I avoided antidepressants is because a common side effect of SSRIs is disruption to sleep. My mood is very responsive to sleep, and I worried that I would just be creating a whole new set of problems for myself; a number of people end up with prescriptions for both sleeping pills and SSRIs. The possibility of sleep disruptions, the fact that my mood was very responsive to other interventions, and other potential side-effects led me to my decision.
I do not think there is a correct answer to the question of whether any particular individual should take SSRIs. I can imagine someone in my shoes whose symptoms were more severe and had tried other options making a different decision. But the persistence of the chemical myth of depression obfuscates this kind of decision-making. Though mental health professionals and academic researchers understand the distinction between whether and how a treatment works, these two things come hand in hand for patients, and it has been disingenuous to pretend otherwise.
One of the main reasons my friend was so upset about the serotonin study was because she was now left with a great many questions. If she wasn’t depressed because of serotonin levels, how was she to understand her propensity to depression? Was something else wrong with brain? Her genetics? Most heartbreakingly, she wondered whether it was that she was simply weak. The serotonin model of depression had not only played a part in her decision to take antidepressants; it shaped how she thought about herself.
I have spent a great many years biting my tongue when friends or acquaintances described their depression in terms of chemical imbalances. I hesitated in part because I was fearful of affecting their treatment, something I did not feel professionally qualified to weigh in on. But my biggest fear was intruding on the way in which they understood themselves and their lives.
Because I have seen myself and my tendency toward depression in different terms, the results of the study have not disrupted my understanding of myself. Though I have sometimes wondered why I seem more inclined to low mood than other people and idly wonder whether it some variation in my particular neurochemistry or genetics, for the most part, when I am going through a depressive period, I recognize its relationship to something that is happening in my life which needs resolving or the fact that I work in a particularly demanding field.
I am not suggesting that SSRIs prevent people from considering what might underlie their depression, or that in all cases depression is situational. But when such a compelling story is put forward by authoritative sources, one that explains so tidily why someone feels the way they do and what can be done about it, people tend not to look elsewhere for explanations or solutions. Just as the chemical imbalance myth has clouded making choices about treatment, it has altered how people understand themselves and their lives.
It is a platitude to say that different treatments work for different people, but I find it interesting that both me and my friend have ended up in similar contented places. One of the reasons the study has been so painful for so many people is the sheer variety of experiences. Those who, like me, have refrained from taking SSRIs feel faintly resentful for the many years that they have been made to feel irrational about their choice.
More tragic are the people like my friend who are now questioning their choices and their understanding of themselves. More tragic still are those patients who had an adverse reaction to SSRIs and have spent many years trying to make the psychiatric establishment acknowledge the myth and the way in which it has hidden the trade-offs associated with SSRIs and other psychiatric drugs. Then there are the many patients for whom SSRIs have been beneficial and continue to advocate for their use in the fear that others will miss out on life changing treatment.
On the other side of the fence, I have colleagues I trust and respect with a wide spectrum of views. What is striking is that once you put the bruised egos and the usual financial vested interests aside, the debates, vicious as they are, seem mostly conducted in utter good faith. Both sides convinced that the other is not only mistaken but in danger of harming vulnerable patients either by peddling dangerous, ill-evidenced treatments or through vilifying treatments that many had found helpful. Though it has been upsetting, I cannot help but find it moving that for most parties involved, the priority is the patient and their well-being.
At this point, we’re all familiar with the trope. A local news station visits a retirement home to celebrate Muriel’s 106th birthday. She’s deaf or blind or both or neither, sitting in a wheelchair in the “good spot” next to the TV set, and a reporter asks her her secret. You’ve lived through both World Wars?!How’d you do it? Then Muriel gets to flash a mischievous grin and tells us she smoked a pack a day for 50 years.
Interacting with centenarians in this way has long made them seem like circus oddities. It trivializes the concept of lifespan and longevity, reducing the science to a throw-your-hands-in-the-hair “Who the hell knows!” It reinforces the idea that our time on this planet isn’t necessarily under our control. If my dad had a stroke and his dad had a stroke then one’s probably coming for me too, right? If I make it to 80, or — god forbid — 90, I’ve just beaten the odds. Right?
Not exactly. Since the mid-1990s, in fact, following the infamous Danish twins study, researchers have understood longevity to be “only moderately heritable.” For a while, this spawned estimates that genetics accounted for somewhere between 20 and 30% of one’s longevity. More recently, scientists have concluded that the true heritability of human longevity at birth is closer to just 7%.
Where does that other 93% come from? Your lifestyle. Your decisions. Your everyday habits, big and small. It’s possible to put years on your life, to surge past both average life expectancy and your own expectations, by resolving to live a certain way. The crazy part? This doesn’t involve some complex Ponce de Leónian quest. You don’t even have to search far and wide for the answers.
You might wonder: Why would I want to live longer? Doesn’t the end of life look drawn out, expensive and horrible? Why would I sign up for decades of suffering? Well, the latest wave of longevity research isn’t focused on living years for the sake of years. It’s concerned with quality years.
Think about it. More years to travel, to exercise, to spend time with your family and whatever new family comes along. An entire life of creativity and challenges to enjoy after retirement. And consider this: those who make it to 100 are no more likely to die at 108 years old than 103. Genetics do start to factor in a bit more once you get way up there in age (hence how the Muriels of the world make it to 106), but overall, your risk of dying from any of the usual diseases plateaus. Longevity wizards only really suffer in the last couple years of their lives.
Take note — this movement is going to happen, with or without you. With an assist from modern medical care, scientists project there will be 25 million centenarians scattered across the world by 2100. (There are currently just 573,000.) But you don’t need to wait for Benjamin Button patents from the big pharmaceuticals. You can start living in the name of longevity today.
Below, 100 ways to live to 100, broken down by how you optimize your lifespan through diet, fitness, good choices and some truly wild wild cards. Before diving in, understand that you can’t do all of them; some of them are likely even incompatible. But the idea is to cherrypick those that work for your life. Ultimately, if nothing else, know this: making the call right now to act in the name of longevity — whether your “right now” is 35 or 65 — won’t just add life to your ledger. It’ll enrich and lighten every year along the way.
1. Eat fresh ingredients grown nearby
The planet’s longest-living communities all have access to food from farms and orchards down the road — that’s to say, within a 10-mile radius of their homes. These ingredients aren’t treated with pesticides or pumped with preservatives; they’re their original nutrient-dense, fiber-rich selves. Sound expensive? So are late-life medical bills.
2. Eat a wide variety of vegetables
So you’ll eat carrots, beets and cucumbers and that’s it. Okay. But if you want to unlock your true longevity potential — and lower your risk of everything from cardiovascular disease to macular degeneration — you need to regularly cycle through the whole menu: cruciferous veggies, dark leafy greens, edible plant stems, roots and marrows.
3. Eat until 80% full
Hara hachi bu is a Japanese saying that translates to “Eat until you’re 80% full.” It’s an alien concept in America, where portion sizes are the biggest in the world and somehow getting larger. But finding your “slightly full” will directly reduce your risk of cancer, heart disease or stroke while giving your body more energy and less bloating in the short term.
4. Eat home-cooked family dinners
As the godfather of nouvelle cuisine, Chef Fernard Point, once famously said: “Butter! Give me butter! Always butter!” Restaurants want customers to leave happy, so they use lots of flavor — salt, sugar and fat. It all adds up. According to one study, eating out twice a day increases your chance of an early death by 95%. Cooking is your best bet.
5. Embrace complex carbohydrates
The bread aisle is a starting point for understanding the difference between foods rich in simple carbohydrates (Wonder Bread) and those rich in complex carbohydrates (100% whole-wheat breads). The latter, for instance, rocks a ton of fiber and fuels the body in a sustainable way. Seek out more complex carbs like brown rice, oats and barley.
6. Consider a plant-based diet
You don’t have to give up meat. But you should know that societies full of centenarians don’t eat very much of it. While meat dominates most American meals, it only appears in Blue Zone diets at a rate of five times a month, two ounces per serving. And when it does, it comes sourced from free-range animals that weren’t treated with hormones or antibiotics.
7. Substitute meat with fish
Keeping fish in the rotation not only takes pressure off your veggie cooking skills — it’s also a huge life-expectancy boon. One study found that “pesco-vegetarians” (who eat up to three ounces of fish daily) live longest, aided by omega-3 fatty acids, vitamins and minerals. If you can, aim for non-farmed, mid-chain fish like trout, snapper and sardines.
8. Try not to eat just before bed
Your last meal of the day should be your smallest, and shouldn’t be eaten within three hours of heading to sleep. If you’re constantly pining for a huge dinner or bedtime snack, you’re probably not fueling properly throughout the day. It’s stress-eating dressed up as a reward, which leads to indigestion in the near term and weight gain over time.
9. Let yourself feel hunger
Don’t get bogged down with YouTube videos on “the right way to intermittently fast.” As renowned Harvard geneticist Dr. David Sinclair told us: “We don’t know the best method. We do know that if you’re never hungry, if you’re eating three meals a day and snacking in between, that’s the worst thing you can do. It switches off your body’s defenses.”
10. Eat dark chocolate
Most people have heard this one. Dark chocolate is no elixir on its own, but cacao tree seeds are part of a family of environmentally stressed plants that “activate longevity pathways in other organisms when consumed.” Replace your cookies and cupcakes with a little square from time to time to reap the rewards of flavanols and resveratrol.
11. Make more PB&Js
Peanut butter and jelly sandwiches are having a moment. A few years ago, ESPN devoted a profile to the NBA’s “secret addiction.” Tom Brady revealed not long after that the PB&J is his pregame meal of choice. And this year, a study concluded that the sandwich can add 33 minutes to your life. Remember to use whole-wheat bread and all-natural jelly.
12. Eat more beans
The backbone of the centenarian diet. Beans are high in fiber, protein, iron, magnesium, potassium and B-vitamins, and low in fat and calories. They fill you up as well as meat and cook easy (serve them on their own with olive oil and a bit of sea salt, or put them in a burrito or salad). David Buettner calls beans “the world’s greatest longevity food.”
13. Eat more nuts
Sure, you’ve heard it forever. That doesn’t make it any less true. One massive study that assessed nut consumption in approximately 119,000 Americans over 30 years found that regular nut-eaters (think a handful or two of almonds a day) reduced their risk of dying from cancer, heart disease and respiratory disease by 20%.
14. Cook with olive oil instead of butter
Olive oil giveth, butter taketh away. While butter increases “bad” cholesterol levels in the blood (low-density lipoproteins), olive oil is a longevity rockstar — in one study, people in the highest quintile for ingesting olive oil’s polyphenols lived an average of 9.5 years longer after the age of 65. Just make sure you’re buying extra virgin olive oil.
15. Put a cap on fun foods
You don’t have to ban salty and sugary treats from your life forever, but recognize that — in order to avoid empty calories and reduce your risk of heart disease — they can’t happen every time you have a tough day at work. That’s a self-defeating choice. Save them for the right time and place, like special celebrations, when you’ll appreciate them the most.
16. Eat slowly
For one, choking to death would really hamper your longevity goal (about one in 2,500 people die each year from choking). But slowing down while eating is also a great way to avoid overeating. Remember — it takes up to 20 minutes for the stomach to process what you’ve eaten. Take deliberate bites. Honor the meal and the effort it took to make it.
17. Drink more water
Here’s the rule: your optimal H20 per diem is one-half ounce to one ounce of water per pound of body weight. A 180-pound male, then, should aim for a little over 11 cups of water over the course of his day. There’s no need to exceed that (you’ll just piss it out), but reach it with regularity and your body’s command centers will repay you in kind.
18. Drink red wine at 5:00 p.m.
Like dark chocolate, red wine comes from a plant source that is rich in cholesterol-lowering flavanols. Some are wary of linking longevity to alcohol, but learning to moderately drink red wine can also recalibrate your relationship to the drug. Having a glass (keep it under three) at the end of the day, preferably with friends, is a stress-relieving behavior.
19. Drink tea every day
Green tea pops up everywhere in lifespan research. One famous study found that drinking the stuff three times a week pushes back your risk of “atherosclerotic cardiovascular disease and all-cause mortality.” If you’re a fan, take up to two cups a day. It makes sure those “cardioprotective” polyphenols stay in your body long-term.
20. Coffee is also a good idea
A stimulant with side effects like jitters and trouble sleeping can help us live longer? Indeed. The chemical compounds in coffee aside from caffeine — a wealth of antixodiants — have a positive impact on mortality, especially when consumed in copious amounts. Drinking multiple cups of coffee each day can help stem chronic diseases from Type 2 diabetes to Parkinson’s.
21. Try the Mediterranean Diet
If you pick up some of the dietary habits above — eat locally, sub fish, use olive oil — you’re already well on your way. Nutritionists are rightfully skeptical on today’s litany of fad diets, but the Mediterranean diet remains well-respected for its capability to alter microbiomes, improve cognitive function, limit risk of heart disease and promote longevity.
22. Let food be
We want food that fits our wacky preferences (separating yolks to make egg whites), has a lot of flavor (peanut butter with added sugar) or would look good on TikTok (deep-fried macaroni and cheese casseroles). But these concepts don’t square away with the traditions of long-living communities, who treat and cook whole foods as they’re naturally cultivated.
23. Stop drinking cow’s milk
Why can’t 68% of the global population digest cow’s milk? We’re not supposed to drink it. Milk — and dairy, at large — is too high in fat and sugar to justify its long-time anointment as the best place to turn for protein and calcium. At the very least, cow’s milk has no impact on longevity, so feel free to sub it for a more environmentally friendly alternative.
24. Know it’s never too late
One month of healthy eating will confer immediate results in the realms of cell regeneration, decreased inflammation and improved digestion. Starting young is great, but it doesn’t matter how old you are. Meet with your doctor beforehand to get your bloodwork done. Then come back after and note the changes, specifically in vascular health.
25. Stick to your dietary changes
Your body will rebel once you ditch your unhealthy ways for a few days. It will undoubtedly feel easier to go back to butter, processed foods and the two vegetables that you actually like. But note all the positive little changes — from your trips up the stairs to your trips to the bathroom. Eating healthy will change your life, then let you live more of it.
26. Sleep more than seven hours a night
Quality sleep is non-negotiable if you want to live a long, healthy life. Entertain a pattern of undersleeping, and exhaustion will seep into everything you do: exercise, diet, interpersonal relationships. Sleeping five hours a night doubles your risk of death. Try to log seven, and keep it right there. Too much sleep isn’t great for longevity, either.
27. Practice yoga
No surprises here. Yoga slows down the effects of stress on cellular aging. Multiple studies (see here and here) have sung the praises of just three months of dedicated yoga. The combination of physical effort, breathwork and meditation slows the tide of inflammation while balancing hormones (like cortisol) that cause chronic stress.
27. Meditate for 15 minutes a day
Even if you can’t commit to an intensive yoga practice, finding time each day to “quiet” your brain is likely a life-extending habit. When we stage personal interventions to decrease brain activity, the brain increases activity of RE1-Silencing Transcription factor, a protein that “allows the brain to function at a higher capacity with less strain.”
28. Schedule an annual physical
“Physician-dodging” is a disturbing status quo for men between the ages of 35 and 54. Only 43% of that middle-aged cohort reported seeing their doctors for annual physicals. Blame it on busy-ness (or more likely, a mix of toxic masculinity and unacknowledged vulnerability), but too often men are late to diagnoses and die earlier because of it.
29. Start strength training
“Functional fitness” takes on an entirely new meaning by age 70, at which point most of us have a lost a quarter of the strength we had at 30 and struggle to perform basic tasks. In fact, people with low muscle strength are 50% more likely to die earlier. Start strength training early and focus particularly on grip strength, which will aid you best in old age.
30. Move every day
Walking for just 11 minutes each day can tangibly protect the body from the mortality risks of hours spent sitting in front of a computer. Leaving the house for a walk each day — like drinking tea and eating beans — is something all Blue Zone communities share. Find a time of day that works for you and pencil in a daily constitutional, rain or shine.
31. Optimize your workplace
A dose of reality on all the longevity chat: most of us aren’t herding goats on a bluff over the Aegean. We spend most of the day answering emails. Within that less-than-ideal situation, make sure your screen is raised to eye level, your back is set against an ergonomic chair and your feet are planted against the floor. Spinal health is critical as you age.
32. Keep an active sex life
Or at the least, an active orgasm life, especially as you age. One Welsh study of men between the ages of 45 and 59 discovered that a “high orgasmic frequency” can lower mortality risk by as much as 50%. Regular sex with a partner, meanwhile, reduces stress and risk of prostate cancer, while lowering blood pressure and improving mood.
33. Hang from a bar for one minute a day
In the “text neck” era, a daily dead hang will bring mobility back to your shoulders. The practice decompresses the spine and builds strength in the upper back. One minute at a time is really hard, so feel free to break the challenge into multiple increments. Oh, and don’t be surprised when the move improves your grip strength, too.
When we breathe through the nose, the nasal passageway humidifies and pressurizes the air. It produces nitric oxide, a molecule that “screens” air particles before they make it to the lungs. Once there, the lungs have an easier, more efficient time circulating oxygen throughout the body. This isn’t an easy switch (more than half of Americans breathe through their mouths), but it’s worth it — the practice can increase lung capacity, which improves cardio-respiratory function.
36. Relax your jaw
“Bruxism,” also known as teeth grinding or jaw clenching, is a natural response in an age of constant anxiety, but it leads to terrible sleep and even tooth fractures. When you’re stressing, take extra care to put space between your teeth and focus on your breathing. And while sleeping, consider a nighttime mouth guard.
37. Exercise in the cold
Cold-temperature exposure turns white fat (the inflammatory fat linked to heart disease) into brown fat (the naturally occurring fat that produces heat) though a process called thermogenesis. Basically, your body has to burn more energy to stay warm, which jumpstarts your metabolism. Norwegian research suggests 120 minutes outside a week in winter.
38. Get off the toilet
According to the “hydromechanics of defecation,” it takes the average person only 12 seconds to do his or her business. But men often linger in the bathroom, to the point that it’s played for laughs in sitcoms. The habit is less than ideal: stretching across the seat inflames the veins of the anal canal and over time can lead to hemorrhoids.
39. Use sunscreen
When melanoma metastasizes, the five-year survival rate nose-dives from 99% down to 25%. Here’s an even crazier statistic: between 1995 and 2014, 60% of those who died from head or neck melanoma were men between the ages of 15 and 39. The sun is no joke; it can snatch life away early if you aren’t using sunscreen and scheduling regular screenings.
One of the beauties of modern exercise? It can be quick. Like, really quick. In the past decade, studies have extolled the benefits of exercising for 15 minutes, four minutes … even four seconds. The rationale remains the same throughout: high-intensity, “all out” bursts of physical effort foster muscle growth, clean up arteries and put years on your life.
42. Learn to play again
The only thing that’s inherently “childish” about playing is that children are more likely to do it. Playing, in whatever form it may take — tennis, pick-up hoops, chasing your kids with a super soaker — is essential for mental health at all ages, and a crucial deviation from exercise measured solely in pain and progress.
43. Worry less about weight loss
Wait, shouldn’t we make weight loss a priority? The issue’s a bit more nuanced. Studies indicate that overly stressing about weight loss often leads to “weight cycling,” defined as a process of losing weight only to regain it all over again. This strains the body. Focus on building sustainable practices instead of aiming to shed fat from your frame.
44. Screen for cancer regularly
This one piggybacks on both the issue of physician-dodging and the need for sunscreen. Cancer is the second leading cause of death in the United States, with lung, colon and liver cancer accounting for the most deaths. It’s imperative that you take it seriously. Start screening regularly at age 45.
45. Make sure to floss once a day
There’s a reason dental hygienists get so terse when you admit to only flossing “once in a while.” Flossing doesn’t just prevents gum disease. It can stop heart disease. When bacteria gets into the bloodstream through the mouth, arteries narrow in an immune response. This taxes vascular health. Flossing for two minutes directly influences life expectancy.
46. Practice sleep hygiene
That doesn’t refer to washing your sheets once a week. Sleep hygiene is “an upkeep of behaviors that help you sleep.” Essentially: treating the process around sleeping as sacred. Learn to keep a calm, cool, uncluttered, sleep-only bedroom and follow methods (from shutting down caffeine intake to getting blackout curtains), that shorten your sleep latency.
47. Start running
Running helps people live longer. That much is clear. But researchers concluded recently that the pace and distance of your run doesn’t necessarily matter. Any sort of running routine (up to four-and-a-half hours total per week) will lead to a 30% reduced risk in all-cause mortality. FYI: going over that amount won’t cause any harm. Just be wary of injuries.
48. Get into swimming
In the battle of cardio routines, though, swimming might take the cake. The activity is perfect for aging: it’s low-impact, burns a ton of calories, works the whole body and encourages flexibility. No wonder that over one 32-year study, swimmers were an amazing 50% less likely to die than regular walkers and runners. Time to fish out the goggles.
49. Forget the six-pack
Listen: chasing a six-pack is a waste of time that has no bearing on how long you’ll live on this planet. Overworking “show muscles” too often comes at the expense of a functional, full-body routine. Double down on a diverse workout scheme and a diet without non-processed ingredients and you’ll naturally arrive at a tighter core, anyway.
50. Ask for help
Recruiting a family member or friend for advice on your fitness journey — or hiring a personal trainer or scheduling a consultation with an exercise physiologist — is not a sign of weakness. It’s the ultimate sign that you’re ready for change, committed to turning your life around and determined to get more life out of it in the process.
51. Don’t ride a motorcycle
Motorcycles look great, but their mortality numbers don’t. According to the NHTSA, motorcyclists are 35 times more likely to have a fatal accident than car drivers. Even survival comes with a cost: 96% of motorcycle accidents result in injury.
Foodstuffs with added sugar, sodium and fat are killing us all. Processed food isn’t supposed to be easy to give up (it comprises over half the “dietary energy consumed” in the United States and United Kingdom). But it’s critical that you cut back. Frozen pizzas, mayonnaise, Oreos and the like drastically increase your risk of cardiovascular disease.
54. Don’t take hard drugs
Aside from the obvious in-moment risk of overdose (deaths from opioids and psychostimulants have been going up since 1990), chronic and high-dose drug use decelerate dopaminergic function. In simpler terms: most of the things you rely on for healthy living — motor control, motivation, arousal, etc. — become seriously compromised over time.
55. Don’t ingest tobacco
Not to sound like an elementary school health teacher, but it really is this simple. Right behind diet, tobacco use is the leading cause of “premature, preventable death” in the United States. And while we normally associate cigarettes with lung cancer, nicotine use can also cause cancer in the throat, esophagus, stomach, pancreas, kidney, bladder and cervix.
56. Don’t smoke e-cigarettes
The majority of e-cigarettes have nicotine in them, but all of them have chemicals that will irritate your lungs. Consider: they contain propylene glycol and vegetable glycerin (which are toxic to cells), acetaldehyde, formaldehyde (which can cause lung or heart disease) and acrolein (a herbicide that’s usually used to kill weeds).
57. Don’t binge drink
The CDC: “A a pattern of drinking that brings a person’s blood alcohol concentration (BAC) to 0.08 g/dl or above.” Think seven drinks or so per binge, with several binges a month. Health experts unilaterally agree that this is a bad idea. One study even determined that drinking 25 drinks per week at age 40 can shorten life expectancy by up to five years.
Every hour, someone dies from a drunk-driving incident in America. That’s over 30% of annual road deaths in the country. Even if you’re a responsible driver, remember to prepare for those who aren’t (always wear a seat belt!) and assess other ways you engage in distracted driving. Sending one text takes your eyes off the road for five seconds.
61. Don’t live in the middle of nowhere
Living close to nature decreases your risk of depression and obesity, indirectly adding years to your life. But there’s such a thing as too much solitude. Rural living can also mean a repressed social life, too much time in the car, relying on Walmart for food, fending for yourself during natural disasters and traveling over an hour for emergency medical care.
62. Don’t blindly pop OTC pills
We’re so accustomed to taking corner-store drugs like Tylenol and Advil that we can forget they’re, well, drugs. Always follow capsule instructions to a tee. The former contains Acetaminophen (which can cause liver issues in high doses), while the latter is a nonsteroidal anti-inflammatory (which can cause gastrointestinal bleeding when taken improperly).
63. Don’t overeat
Calorie restriction can play a small part in adding years to your life, but unchecked calorie intake plays a very loud role in taking them away. The average American eats 3,600 calories a day (up nearly 25% from the 1960s), and the national obesity rate sits at 42.4%. Obesity coincides with common comorbidities like Type 2 diabetes, hypertension and cancer.
64. Don’t eat more protein than you need
The scientific research on this is pretty clear, as much as it may shock the biggest guy at your gym. A reduced protein intake “plays a critical role in longevity and metabolic health.” Most American men currently average twice the amount of protein they actually need in a day. That comes with too much IGF-1, a growth factor that accelerates aging.
65. Don’t stay in a stressful job
A study published in 2015 found that sticking with a tough job — with an unreasonable boss, little social support or looming layoffs — can literally take two years off your life. A paycheck is a paycheck, but when a job starts exerting massive mental stress over you, the body can’t tell if the initial trigger is mental or physical. It’ll fall apart either way.
66. Don’t hold a grudge
Happy people live longer. Improve your happiness by practicing “epistemic humility,” an intellectual virtue predicated on the idea that one can ever know something for sure. It’s meant to help us admit our imperfections and forgive others. Sounds too good to be true in the 2020s? All the more reason to give it a try.
67. Don’t blame your genes
When less than 25% of your genetics are accountable for your personal longevity, it doesn’t make much sense to deterministically pin your fate (or blame your behaviors) on what happened to your parents or grandparents. Learn your familial risks, yes, but approach your daily actions and decisions with confidence and hope.
68. Don’t sit around all day
Online publications really ran with the “sitting is the new smoking” tagline. Not quite, but sitting should be taken seriously as a public health issue. American adults sit seven hours a day, which disrupts the body’s ability to break down body fat, slows metabolism and elevates blood pressure. Get moving, even if it’s just for 10 minutes.
69. Don’t doomscroll
New phrase for you? Doomscrolling is “excessively scrolling through news or social media feeds looking for negative updates.” It’s at the intersection of smartphone addictions, a terrible news cycle and our primordial need to anticipate danger. But this sort of behavior wreaks havoc on your mental health and (unsurprisingly) never solves anything.
70. Don’t binge-watch Netflix
A full eight years ago, 61% of Netflix users admitted to binge-watching content on the platform. We’ve added five major streaming services since then; each has a revolving door of content and most employ hyped full-season releases. While cranking through episodes feels like a reward, it causes eye strain, backaches, weight gain and sleep deprivation.
The “Should you let your kids play football?” became a culture war topic in the early 2010s on the heels of unprecedented CTE research. Honest answer: probably not. At least, avoid the full-contact version of the game, which has the highest concussion rate outside of rugby and can cause irreversible damage to the brain.
73. Don’t fool around in National Parks
Or state parks. Or the woods behind your house. Or any public lands where you can hike, swim and camp without a professional ranger on hand to help at a moment’s notice. People die constantly from drowning, falls, exposure, animal encounters … selfie sticks. The issue is more relevant than ever, as novice hikers flock to nature in the pandemic era.
We knew we hated shampoo. Chemicals called phthalates are found in shampoos, fragrances, cleansers and plastics. When they get into the body, they reduce the body’s stress hormone cortisol, meddle with metabolism, negatively affect the reproductive system, and can lead to extremely preventable premature deaths.
77. Live with a purpose
The Okinawans say ikigai, the Nicoyans in Costa Rica say plan de vida. Each phrase translates to “why I wake up in the morning.” Finding that “why” can feel random and frustrating, but it often brings people to pursuits and causes outside of themselves. And — science backs this up — once you believe your life matters, you get to live more of it.
78. Manage negative thought loops
Negative thought loops trick us into thinking we’re being productive (we psychoanalyze uncomfortable memories, prepare for imaginary dangers, relitigate life decisions), but in reality we’re just willingly drowning ourselves in a puddle of anxiety, activating a hormone-fueled “fight or flight” response that can’t be addressed in the given moment.
79. Have a plan after retirement
Not necessarily a financial plan, though that’s also a good idea. One surprising study displayed that working longer can help people live longer. Remember, jobs can be real-world lifelines for many — they offer social engagement, days out of the house, challenging projects. It’s important to have goals and communities for filling your time after retiring, too.
Team sports are a longevity motherlode. They combine consistent social interaction, vigorous exercise and play, all of which convey dynamite benefits for your physical and mental health. One study even discovered that making an adult soccer league your primary mode of exercise (over solo activities like jogging) could add five years to your life.
84. Tell the truth
Another reason not to get into politics — lying takes years off your life. The emotional stress that comes from telling mistruths often manifests as physical stress. Whatever the momentary reward, lying increases your risk of anxiety and depression, can sabotage relationships over time and shatters your self-esteem.
85. Listen to live music twice a month
Take the fortnight frequency with a grain of salt (it comes from a study commissioned by British entertainment operator O2), but we do know that live concerts are mindful, socially rich experiences. Assuming you don’t need to binge drink or trip on acid every time you attend one, plugging concerts into the calendar each month is a great idea.
86. Take colder showers
Make like Ian Fleming’s James Bond and finish your showers with an ice-cold “Scottish” rinse. Up to a minute (after a morning workout) is best, if you can handle it. The ritual will lower blood pressure, stimulate your immune system and can even hack your mood, releasing happy neurotransmitters like dopamine, adrenaline, norepinephrine and serotonin.
87. Read before bed
According to one study from the Yale University School of Public Health, “people who read books for at least 30 minutes a day live nearly two years longer than non-readers.” Reading lowers heart rate and eases tension in the muscles, fosters empathy (especially if you’re reading fiction) and helps defeat insomnia. Start with a chapter a day.
The phrase refers to performing an activity that necessitates presence of mind. Think: cooking, gardening, walking the dog. While these sound like chores, they’re actually back doors to positive thinking and productivity. It’s an effective treatment for depression and other mood disorders, whereas languishing only worsens symptoms.
90. Avoid social jetlag
Social jet lag occurs when the body’s sleep-wake cycle is suddenly thrown out of whack. When you choose to stay up late on a Saturday, you’re pushing the “midpoint” of your sleep forward. You then have to scramble back to your usual internal clock in time for Monday morning, which affects everything from body temperature to metabolism.
91. Learn a language
Similar to “eat a bowl of almonds,” we’ve all heard this one. But it’s also absolutely true. Bilingual brains age slower than monolingual brains, delaying neurological diseases like dementia and Alzheimer’s. It’s never too late, and don’t stress if fluency feels out of reach — the simple act of learning and studying a second language has a positive impact on the brain.
92. Show up to events
Researchers are convinced: “Social connections are probably the single-most important feature of living a long, healthy, happy life.” Showing up to functions with family and friends (as opposed to stressing out and skipping them) proves you can be a light, reliable presence in other people’s lives. The invites will keep coming, and you’ll be better off for it.
93. Maintain friendships
Swimming in centenarians, Sardinia was the first Blue Zone region ever identified. The island’s men have a habit of finishing each day at a local bar to talk with lifelong friends. In America, where 15% of middle-aged men report having no close friends, that sort of dynamic everyday interaction (whether at a bar or book club) could prove revelatory.
Or visit the ballet. Or visit some experimental art show that your friend’s friend is putting on (even if you have no interest). Those who afford themselves a regular “culture fix” have a 14% lower risk of passing away earlier than a typical lifespan. There is a correlation-over-causation argument to be made, but taking in art is always beneficial.
96. Find your spiritual side
You may want nothing to do with religion. But the findings are indisputable. People of faith people live longer, and in some cases, by up to four years. Congregations show up at the same time each week, they tell stories, they volunteer in their communities. From a longevity perspective, these rituals are extremely potent. It’s worth finding your equivalent.
97. Change your mind
Never in the history of the internet has anyone said “My bad, I’ve changed my mind.” Perhaps people should start. Challenging yourself to look past your imperfect point of view is a next-level stress-reliever that unshackles your entire mindset. Stop arguing in circles. Embrace that other people know things. Then live longer for it.
98. Have a family
It’s a good idea to grow old around younger people. Adults with at least one child tend to have more social interactions and lower mortality rates. On a somewhat less wholesome note, men who end up with younger partners also live longer, too. Younger spouses are a positive psychological influence, and more capable caretakers in the twilight years.
99. Summon some empathy
The whole of society is in an “empathy crisis” right now, so it’s okay if thinking of others takes a little extra effort. But monitoring and augmenting your empathic capacity isn’t just beneficial for your friends, family and colleagues — it’s associated with life satisfaction and positive “interaction profiles” (how you relate to others), regardless of age.
100. Celebrate aging
Not just in the birthday cake sense. Those who approach aging with a positive outlook end up aging easier than others. Proactively acknowledge what’s to come instead of fretting about the wrinkles under your eyes. Maybe you’ll make it to 100. Maybe you won’t. But your absolute best chance comes from living your best life along the way.
Angel Lawrence J. (1984), “Health as a crucial factor in the changes from hunting to developed farming in the eastern Mediterranean”, Proceedings of Meeting on Paleopathology at the Origins of Agriculture: 51–73
Conrad, Lawrence I. (2006). The Western Medical Tradition. Cambridge University Press. p. 137. ISBN978-0-521-47564-8. They could do little, for example, to change the facts that life expectancy was not much above 35 years, and the majority of children died before reaching adulthood.
Ikeda, Nayu; Saito, Eiko; Kondo, Naoki; Inoue, Manami; Ikeda, Shunya; Satoh, Toshihiko; Wada, Koji; Stickley, Andrew; Katanoda, Kota; Mizoue, Tetsuya; Noda, Mitsuhiko; Iso, Hiroyasu; Fujino, Yoshihisa; Sobue, Tomotaka; Tsugane, Shoichiro; Naghavi, Mohsen; Ezzati, Majid; Shibuya, Kenji (August 2011). “What has made the population of Japan healthy?”. The Lancet. 378 (9796): 1094–105. doi:10.1016/S0140-6736(11)61055-6. PMID21885105. S2CID33124920. Reduction in health inequalities with improved average population health was partly attributable to equal educational opportunities and financial access to care.
“The human sex ratio from conception to birth” Steven Hecht Orzack, J. William Stubblefield, Viatcheslav R. Akmaev, Pere Colls, Santiago Munné, Thomas Scholl, David Steinsaltz, and James E. Zuckerman PNAS April 21, 2015 112 (16) E2102-E2111; first published March 30, 2015 https://doi.org/10.1073/pnas.1416546112.
In the summer of 2020, as the pandemic raged, infecting more than 200,000 people a day across the globe, Pfizer CEO Albert Bourla and BioNTech CEO Uğur Şahin boarded an executive jet en route to the hilly countryside of Klosterneuburg, Austria. Their destination: a small manufacturing facility located on the west bank of the Danube River called Polymun Scientific Immunbiologische Forschung.
Bourla and Şahin were on a mission to get the company to manufacture as many lipid nanoparticles as possible for their new Covid-19 vaccine, which was on a fast track to receive emergency authorization from the U.S. Food and Drug Administration.
The Pfizer-BioNTech vaccine had been engineered with messenger RNA technology that instructs the body’s immune system to combat the coronavirus. But to get it safely into human cells, the mRNA needed to be wrapped in microscopic fragments of fat known as lipids. The Austrian manufacturing plant was one of the few places on earth that made the required lipid nanoparticles, and Bourla insisted Şahin go with him personally to press their case.
“The whole mRNA platform is not how to build an mRNA molecule; that’s the easy thing,” Bourla says. “It is how to make sure the mRNA molecule will go into your cells and give the instructions.”
Yet the story of how Moderna, BioNTech and Pfizer managed to create that vital delivery system has never been told. It’s a complicated saga involving 15 years of legal battles and accusations of betrayal and deceit. What is clear is that when humanity needed a way to deliver mRNA to human cells to arrest the pandemic, there was only one reliable method available—and it wasn’t one originated in-house by Pfizer, Moderna, BioNTech or any of the other major vaccine companies.
A months-long investigation by Forbes reveals that the scientist most responsible for this critical delivery method is a little-known 57-year-old Canadian biochemist named Ian MacLachlan. As chief scientific officer of two small companies, Protiva Biotherapeutics and Tekmira Pharmaceuticals, MacLachlan led the team that developed this crucial technology. Today, though, few people—and none of the big pharmaceutical companies—openly acknowledge his groundbreaking work, and MacLachlan earns nothing from the technology he pioneered.
“I look at the news, and 50% of it is vaccines—it’s everywhere—and I have no doubt the vaccines are using the technology we developed.”
“I just wasn’t going to spend the rest of my life dealing with it, but I can’t escape it,” MacLachlan says. “I open my browser in the morning and look at the news, and 50% of it is vaccines—it’s everywhere—and I have no doubt the vaccines are using the technology we developed.”
Moderna Therapeutics vigorously disputes the idea that its mRNA vaccine uses MacLachlan’s delivery system, and BioNTech, the vaccine maker partnered with Pfizer, talks about it carefully. Legal proceedings are pending, and big money is at stake.
Moderna, BioNTech and Pfizer are on their way to selling $45 billion worth of vaccines in 2021. They don’t pay a dime to MacLachlan. Other coronavirus vaccine makers, such as Gritstone Oncology, have recently licensed MacLachlan’s Protiva-Tekmira delivery technology for between 5% and 15% of product sales. MacLachlan no longer has a financial stake in the technology, but a similar royalty on the Moderna and Pfizer-BioNTech vaccines could yield as much as $6.75 billion in 2021 alone. In an ironic twist of fate, though, President Biden’s proposal to waive Covid-19 vaccine patents would make it unlikely that the intellectual property related to MacLachlan’s advances could be a source of riches.
Despite their denials, scientific papers and regulatory documents filed with the FDA show that both Moderna and Pfizer-BioNTech’s vaccines use a delivery system strikingly similar to what MacLachlan and his team created—a carefully formulated four-lipid component that encapsulates mRNA in a dense particle through a mixing process involving ethanol and a T-connector apparatus.
For years, Moderna claimed it was using its own proprietary delivery system, but when it came time for the company to test its Covid-19 vaccine in mice, it used the same four kinds of lipids as MacLachlan’s technology, in identical ratios.
Moderna insists the preclinical formulation of the vaccine was not the same as the vaccine itself. Subsequent regulatory filings by Moderna show its vaccine uses the same four types of lipids as MacLachlan’s delivery system but with a proprietary version of one of the lipids and the ratios “slightly modified” in a still undisclosed manner.
It’s a similar story for Pfizer and BioNTech. FDA documents show their vaccine uses the same four kinds of lipids in nearly the exact ratios that MacLachlan and his team patented years ago, albeit with one of those lipids being a new proprietary variation.
Not everyone ignores MacLachlan. “A lot of credit goes to Ian MacLachlan for the LNP [lipid nanoparticle],” says Katalin Karikó, the scientist who laid the groundwork for mRNA therapies before joining BioNTech in 2013. But Karikó, now a frontrunner for a Nobel Prize, is angry that MacLachlan didn’t do more to help her use his delivery system to build her own mRNA company years ago. “[MacLachlan] might be a great scientist, but he lacked vision,” she says.
Seven years ago, MacLachlan quit his position at Tekmira, walking away from his brilliant discovery and any potential financial rewards. Messy legal battles and political infighting within the biopharma industry over the delivery system had taken a toll on him. His emotions are complex. He may be overlooked, but he knows that he helped save the world.
“There’s a team of people who gave a great deal of their lives to the development of this technology. They gave their heart and soul,” MacLachlan says. “These people worked like dogs and gave the best part of themselves to develop it.”
Perched on a hilltop, Hohentübingen Castle towers above the town of Tübingen, Germany. In October 2013, MacLachlan, then the chief scientific officer of Tekmira Pharmaceuticals, trudged up the hill to the castle to attend a cocktail party at the first International mRNA Health Conference. During the evening, MacLachlan struck up a conversation with Stéphane Bancel, the CEO of an upstart mRNA company called Moderna Therapeutics. MacLachlan suggested Tekmira and Moderna collaborate using his innovative drug delivery system. “You are too expensive,” Bancel told him.
The exchange gave MacLachlan a bad feeling. So did the presence of a former colleague, Thomas Madden, who had been fired by Tekmira five years earlier. By this point MacLachlan had spent more than a decade working on his delivery system, yet people like Bancel seemed more interested in working with the London-born Madden.
The rivalry between these two scientists is the root of the controversy over the delivery technology that today’s Covid-19 vaccines rely on. MacLachlan and Madden met 25 years ago, when they worked together at a small Vancouver-based biotech called Inex Pharmaceuticals. With a Ph.D. in biochemistry, MacLachlan joined Inex in 1996, his first job after completing a postdoctoral fellowship in a gene lab at the University of Michigan.
Inex was cofounded by its chief scientific officer, Pieter Cullis, now 75, a long-haired physicist who taught at the University of British Columbia. From his perch there Cullis started several biotechs, cultivating an elite community of scientists that made Vancouver a hotbed of lipid chemistry.
Inex had a small-molecule chemotherapy drug candidate, but Cullis was also interested in gene therapy. His goal was to deliver large-molecule genetic material, like DNA or RNA, inside a lipid bubble so it could be safely ferried as medicine to the inside of a cell—something biochemists had dreamed about for decades but had been unable to accomplish.
Using a new method that mixed detergent with liquid, Cullis and his team at Inex successfully encapsulated small pieces of DNA in microscopic bubbles called liposomes. Unfortunately, the system could not consistently deliver bigger molecules, the type needed for gene therapy, in medically useful ways. They tried other approaches, including using ethanol, but didn’t succeed.
“We assembled all the LNP [lipid nanoparticle] pieces at Inex, but we didn’t get it to work” for genetic material, Cullis says.
Inex was a business, not a research lab, so it shifted its emphasis to the more promising chemotherapy drug. The gene therapy group was largely disbanded. MacLachlan ran what was left of it until, in 2000, he too decided to quit. Rather than let him completely walk away, Cullis persuaded MacLachlan to take the firm’s delivery assets and spin them out in a new company. Thus was born Protiva Biotherapeutics (MacLachlan became chief scientific officer), in which Inex retained a minority stake. MacLachlan recruited Mark Murray, now 73, a longtime American biotech executive with a Ph.D. in biochemistry, to be CEO.
It wasn’t long before two Protiva chemists, Lorne Palmer and Lloyd Jeffs, made a crucial discovery that led to a new mixing method. They put lipids dissolved in ethanol on one side of a physical T-connector apparatus, and, on the opposite side, genetic material dissolved in saltwater, then shot streams of the two solutions at each other. It was the moment they had been hoping for. The collision resulted in lipids forming a dense nanoparticle that instantly encapsulated the genetic material. The method was elegantly simple, and it worked.
In the midst of all this furious legal fighting, Hungarian biochemist Katalin Karikó showed up at MacLachlan’s door. Karikó was early to grasp that MacLachlan’s delivery system was key to mRNA therapies.
“The various methods that had been used previously were all highly variable and ineffective,” MacLachlan says. “Completely unsuitable for manufacturing.
The team he led quickly went on to develop a new lipid nanoparticle made of four specific kinds of lipids. Though these were among the lipids Inex had also been using in its experiments, MacLachlan’s LNP had a dense core that differed significantly from the sac-like liposome bubbles developed by Inex. MacLachlan’s team had figured out the specific ratios of the four kinds of lipids that worked best relative to one another. Everything was dutifully patented.
Moderna and Pfizer’s Covid vaccines use a type of gene therapy based on the messenger RNA molecule. Protiva’s scientists, though, initially gravitated toward a different type of gene therapy using RNA interference, or RNAi. While mRNA instructs the body to create therapeutic proteins, RNAi aims to silence bad genes before they cause disease. With MacLachlan’s delivery system in hand, Protiva started collaborating with Alnylam, a Cambridge, Massachusetts–based biotech, to make RNAi therapy viable.
Meanwhile, MacLachlan’s old company, Inex, was imploding after the FDA denied accelerated approval to its chemotherapy drug. Inex fired most of its staff and then—despite having spun off Protiva only a few years earlier—looped back to drug delivery. It, too, started working in partnership with Alnylam. In 2005 Cullis quit, leaving none other than MacLachlan’s archrival Thomas Madden to run Inex’s delivery efforts.
In 2006, Protiva and Alnylam published a landmark study in Nature demonstrating the first effective gene silencing in monkeys. The study used the delivery system MacLachlan’s team had developed.
Alnylam went on to develop Onpattro, an RNAi drug used to treat nerve damage in adults with a certain hereditary condition. The drug would become the first RNAi medicine ever approved by the FDA. Regulatory filings show Alnylam used MacLachlan’s delivery system for Onpattro—with one exception. For one of the four kinds of lipids, Alnylam used a modified version it developed with Thomas Madden.
In October 2008, Mark Murray, the CEO MacLachlan had recruited to run Protiva, stood in a room at Tekmira Pharmaceuticals, a small publicly traded shell company he had just taken over. Like Protiva, Tekmira had been created by Inex, which had finally burned out a year earlier, but not before transferring all its remaining assets to Tekmira. Assembled before Murray were some 15 former Inex scientists who had come along in the deal, including Thomas Madden.
“Unfortunately, we are not going to be able to keep you guys any longer,” Murray told them.
Madden’s firing was one result of a massive legal brawl sparked by the fact that both Inex and Protiva had been working separately with Alnylam on drug delivery. The dispute would continue for years. In each iteration, Murray and MacLachlan would accuse Madden and Cullis of having improperly taken their ideas. Cullis and Madden, offended by the accusations, denied them. Sometimes they sued back, claiming Murray and MacLachlan had acted wrongly.
The first round of litigation resulted in a 2008 settlement that saw Protiva take over Tekmira, with Murray as CEO, MacLachlan as chief scientific officer and Madden soon fired. Despite the bruising, Madden and Cullis founded a new company in 2009 to continue working with Alnylam.
Tekmira responded by suing Alnylam, claiming the Massachusetts biotech conspired with Madden and Cullis to cheaply gain ownership of the delivery system developed by MacLachlan. Alnylam denied wrongdoing and—of course—filed counterclaims, saying it simply wanted to work with Madden and Cullis, who had created an improved variation of one of the four kinds of delivery-system lipids.
That round of the legal brawl was settled in 2012, with Alnylam paying Tekmira $65 million and agreeing to assign dozens of its patents back to Tekmira. Those patents included ones for the improved lipid that Madden had developed for Onpattro. Under the deal, Cullis and Madden’s new company was granted a narrow license to use the MacLachlan delivery system to create new mRNA products from scratch.
Feeling defeated, MacLachlan quit Tekmira. He sold his stock, purchased a used Winnebago Adventurer for $60,000 and set off with his wife, two kids and their dog for a 5,200-mile road trip. “I was exhausted and demoralized.”
It was in the midst of all this furious legal fighting that Hungarian biochemist Katalin Karikó first showed up at MacLachlan’s door. Karikó was early to grasp that MacLachlan’s delivery system held the key to unlocking the potential of mRNA therapies. As early as 2006, she began sending letters to MacLachlan urging him to encase her groundbreaking chemically altered mRNA in his four-lipid delivery system. Embroiled in litigation, MacLachlan passed on her offer.
Karikó didn’t give up easily. In 2013, she flew to meet with Tekmira’s executives, offering to relocate to Vancouver and work directly under MacLachlan. Tekmira passed. “Moderna, BioNTech and CureVac all wanted me to work for them, but my number one choice, Tekmira, didn’t,” says Karikó, who took a job at BioNTech in 2013.
By this time, Moderna CEO Stéphane Bancel was also trying to solve the delivery puzzle. Bancel held discussions with Tekmira about collaborating, but talks stalled. At one point, Tekmira indicated it wanted at least $100 million up front, plus royalties, to strike a deal. Instead, Moderna partnered with Madden, who was still working with Cullis at their drug delivery company, Acuitas Therapeutics.
In February 2014, MacLachlan turned 50. His life partner, Karley Seabrook, lured him to Vancouver’s Imperial theater, which was packed with friends and family. She surprised him in a wedding dress, and their two children greeted MacLachlan with cards that read WILL YOU MARRY MOMMY? Seabrook had never thought it important that they get married, but a brush with cancer had altered her perspective—and the wedding would alter his.
For the workaholic scientist, dealing with lawyers and endless corporate maneuvering had taken its toll. Feeling defeated, MacLachlan quit Tekmira in 2014. He sold his stock in the company, purchased a used Winnebago Adventurer for $60,000 and set off with his new wife, two kids and their dog for a 5,200-mile road trip across Canada.
“I was exhausted and demoralized,” he says. With MacLachlan gone, CEO Murray renamed Tekmira, calling it Arbutus BioPharma, and decided the company should focus on creating hepatitis B treatments with New York drug development company Roivant Sciences. Yet he held on to the patents for the four-lipid drug delivery system.
Then Madden’s company, Acuitas, sublicensed the delivery technology to Moderna for the development of an mRNA flu vaccine. Murray was confident Madden had no right to do so, and in 2016 he gave notice that he intended to terminate Acuitas’ licensing agreement. Per custom, two months later, Acuitas sued in Vancouver, denying that it had violated any deal. On cue, Murray countersued, initiating a fresh round of legal combat. Importantly, though, this batch of lawsuits directly involved mRNA.
After battling for two more years, the parties settled. Murray terminated Thomas Madden’s license to MacLachlan’s delivery technology for any future medicines other than four products Moderna had already begun to develop (Murray also lost the rights to some of Madden’s technology). Murray and Roivant then created another company, Genevant Sciences, specifically to house the intellectual property related to the four-lipid delivery system and commercialize it.
Some companies were quick to come on board. Within a few months BioNTech CEO Şahin struck a deal with Genevant to use the delivery system for five of BioNTech’s existing mRNA cancer programs. The companies also agreed to work together on five other mRNA programs targeting rare diseases. There was no provision in the agreement about using the delivery technology for something completely unforeseen—something like Covid-19.
Moderna pursued a different strategy. It filed lawsuits with the U.S. Patent and Trademark Office seeking to nullify a series of patents related to MacLachlan’s delivery system, now controlled by Genevant. But in July 2020, as Moderna was pushing its vaccine through clinical trials, an adjudicative body largely upheld the most important patent claims. (Moderna is appealing.)
After the Moderna and Pfizer-BioNTech vaccines were authorized, Drew Weissman, a prominent mRNA researcher at the University of Pennsylvania, concluded in a peer-reviewed journal that both use delivery systems that are “similar to the Alnylam Onpattro product” but with a proprietary version of one of the lipids. Weissman noted both companies were using T-junction mixing.
Thomas Madden worked on the Pfizer-BioNTech vaccine delivery system and says he used enhanced versions of two of the four kinds of lipids. Madden says neither Onpattro nor the Pfizer-BioNTech vaccine would have been green-lighted by the FDA without his team’s improvements to the lipids.
MacLachlan dismisses the new variations as “iterative innovation.”
In a written statement to Forbes, Ray Jordan, Moderna’s corporate affairs chief, stated, “I can confirm that we did take a license to Tekmira’s IP for certain of our older products. But our newer products (including the Covid vaccine) have moved on with new technology.”
BioNTech declined to comment. Mikael Dolsten, Pfizer’s chief scientific officer, says the Pfizer-BioNTech vaccine is fully covered by patents and that in creating the first authorized mRNA product, Pfizer modified the delivery system to produce 3 billion doses annually.
“It’s different to have a process that may work for a very small scale than a large scale, and some of the assumptions that may look similar are based on how the scientific field evolved and [on] contributions from many different sources,” Dolsten says. “One needs to be careful in assuming that [if] things have similar names and similar molar ratios, it means it’s the same thing.”
Genevant declined to comment, but it could be fighting an uphill battle. In May, the Biden Administration backed waiving intellectual property protection on Covid-19 vaccines. Ironically, such a move might benefit, not hurt, Moderna, BioNTech and Pfizer by preventing Genevant from making any claims on their gigantic vaccine cash pile.
That’s just as well for Ian MacLachlan, whose role in what may be the most important medical advance in a century has been all but erased by the biotech industry.
“I definitely feel I made a contribution,” he says. “I have mixed feelings because of the way it’s being characterized, and I know the genesis of the technology.”
Artificial intelligence has been used to predict the structures of almost every protein made by the human body. The development could help supercharge the discovery of new drugs to treat disease, alongside other applications. Proteins are essential building blocks of living organisms; every cell we have in us is packed with them.
Understanding the shapes of proteins is critical for advancing medicine, but until now, only a fraction of these have been worked out. Researchers used a program called AlphaFold to predict the structures of 350,000 proteins belonging to humans and other organisms. The instructions for making human proteins are contained in our genomes – the DNA contained in the nuclei of human cells.
There are around 20,000 of these proteins expressed by the human genome. Collectively, biologists refer to this full complement as the “proteome”. Commenting on the results from AlphaFold, Dr Demis Hassabis, chief executive and co-founder of artificial intelligence company Deep Mind, said: “We believe it’s the most complete and accurate picture of the human proteome to date.
“We believe this work represents the most significant contribution AI has made to advancing the state of scientific knowledge to date. “And I think it’s a great illustration and example of the kind of benefits AI can bring to society.” He added: “We’re just so excited to see what the community is going to do with this.”
Proteins are made up of chains of smaller building blocks called amino acids. These chains fold in myriad different ways, forming a unique 3D shape. A protein’s shape determines its function in the human body. The 350,000 protein structures predicted by AlphaFold include not only the 20,000 contained in the human proteome, but also those of so-called model organisms used in scientific research, such as E. coli, yeast, the fruit fly and the mouse.
This giant leap in capability is described by DeepMind researchers and a team from the European Molecular Biology Laboratory (EMBL) in the prestigious journal Nature. AlphaFold was able to make a confident prediction of the structural positions for 58% of the amino acids in the human proteome.
The positions of 35.7% were predicted with a very high degree of confidence – double the number confirmed by experiments. Traditional techniques to work out protein structures include X-ray crystallography, cryogenic electron microscopy (Cryo-EM) and others. But none of these is easy to do: “It takes a huge amount of money and resources to do structures,” Prof John McGeehan, a structural biologist at the University of Portsmouth, told BBC News.
Therefore, the 3D shapes are often determined as part of targeted scientific investigations, but no project until now had systematically determined structures for all the proteins made by the body. In fact, just 17% of the proteome is covered by a structure confirmed experimentally. Commenting on the predictions from AlphaFold, Prof McGeehan said: “It’s just the speed – the fact that it was taking us six months per structure and now it takes a couple of minutes. We couldn’t really have predicted that would happen so fast.”
“When we first sent our seven sequences to the DeepMind team, two of those we already had the experimental structures for. So we were able to test those when they came back. It was one of those moments – to be honest – where the hairs stood up on the back of my neck because the structures [AlphaFold] produced were identical.”
Prof Edith Heard, from EMBL, said: “This will be transformative for our understanding of how life works. That’s because proteins represent the fundamental building blocks from which living organisms are made.” “The applications are limited only by our understanding.” Those applications we can envisage now include developing new drugs and treatments for disease, designing future crops that can resist climate change, and enzymes that can break down the plastic that pervades the environment.
Prof McGeehan’s group is already using AlphaFold’s data to help develop faster enzymes for degrading plastic. He said the program had provided predictions for proteins of interest whose structures could not be determined experimentally – helping accelerate their project by “multiple years”.
Dr Ewan Birney, director of EMBL’s European Bioinformatics Institute, said the AlphaFold predicted structures were “one of the most important datasets since the mapping of the human genome”. DeepMind has teamed up with EMBL to make the AlphaFold code and protein structure predictions openly available to the global scientific community.
Dr Hassabis said DeepMind planned to vastly expand the coverage in the database to almost every sequenced protein known to science – over 100 million structures.
By : Paul Rincon / Science editor, BBC News website