Tuesday, January 26, 2016

Uncertain Health in an Insecure World – 73

“Life, With Parole”

With risk comes stress, and with stress comes damage.

Resilience is defined as “the ability to become strong, healthy, or successful again after something bad happens.” Once only popular in self-help motivation spheres, it has since deeply penetrated organizational culture parlance. Whether an individual or a corporation thrives over time often depends on personal or collective endurance, in the face of accumulated adversity.

Recently, the term resilience has gained traction in the scientific community, related to an organism’s durability… its very survival… in the face of life’s mounting bad odds of disease.

First, just what are the bad odds?
A large U.S. actuarial survey by Milliman, Inc. (2010) of the risk of critical illnesses – cancer, heart attacks and strokes – confirms the old medical adage that “life has a poor prognosis”. For healthy 25 year-old non-smoking males, the risk is 24% by age 65; the risk doubles to 49% for smokers. By comparison, only 35% of female smokers develop a critical illness. If a male reaches the age of 55 years without a chronic disease, the risk of developing a critical illness in the ensuing decade is 17% for non-smokers, and 36% for smokers. For 55 year-old women, the corresponding rates are 12% and 23%.

Such data are somewhat intuitive. Smoke and you die, especially if you’re a guy!

The risk of critical illnesses is just one slice of the bigger picture of chronic diseases – diabetes, hypertension, auto-immunity, arthritis, lung disease, etc. In a 2013 Pew Research Center report, 45% of U.S. adults reported living with at least one chronic illness. The rate increases to 75% among U.S. adults aged >65 years. Interestingly, advanced age and lower education levels were co-variables of both higher chronic disease and lower internet access. These chronic conditions increase the likelihood of acute emergency room visits and critical illnesses. 

Probabilistic concepts of chronic disease causation have been well studied by epidemiologists.

The bitter 1950’s debate about the link between cigarette smoking and lung cancer was among the first tests of this quantitative science. At places like Massachusetts Institute of Technology, the math behind cause & effect (i.e., risk factors relationship to chronic diseases; above) has been extensively studied since the early days of the big data-analytics era circa 1990 (Long, WJ. The Probability of Disease, 15th Symposium on Computer Applications in Medical Care, 1991). The 2012 Australian Institute of Health and Welfare report on the Risk Factors Contributing to Chronic Disease made the public health case for staying sober, not smoking, exercising and maintaining a normal BMI – in 126 colorful pages!!

A large Canadian insurance firm (Manulife; www.manulife.ca) has an app for that (below).

Just like in criminal justice, the presence of “priors” – age, gender, and smoking status – are the primary determinants of the sentence… of death, or life.

The Resilience Project was established by Steven Friend of Sage Bionetworks and Eric Schadt of the Icahn School of Medicine at Mount Sinai.

The project’s goal is to look all over the world for unique “heroes” – those who have bad genes and lifestyle risks, but who also demonstrate freedom from chronic diseases. This highly novel approach – studying why people who should be dead or dying stay healthy and alive – is the antithesis of decades of epidemiological and biomedical research into why humans get sick.

In the words of Steven Friend (TED Talk, Vancouver, March 2014, above), who began his medical career studying genetic susceptibility to childhood cancers, “We have the power to diagnose, yet not the power to fully treat.” Friend poses the case for not studying those who are sick and their risks – “Maybe we should be studying those who are well.” A few individuals may have prior risks, but also have some “hidden protection factor” in their genomes.

In 2013, Friend and Schadt began to collect cheek swabs (above) from adults >40 years old who were healthy as kids, screening them for genes posing a risk of childhood disease. Citing protective gene mutations against AIDS in people with high HIV viral loads, and against heart diseases in those with high blood lipids, they work globally in an open crowd-sourced way to “decipher these positive outliers.” By decoding the tissue samples of Project participants, to date they have found dozens of candidate “hero genes.

Friend and Schadt are convinced that individuals, not “anointed experts”, are the key to the success of The Resilience Project, and to future related disease prevention strategies. Says Friend, “We don’t know how to read the read the sentences… (or) how to follow the narrative” of the genetic code. As such, “We don’t know how to develop drugs that restore function.

Absent resilience, the best sentence we humans can plead to is death.

The Resilience Project offers evidence-based justice in the face of this death sentence. 

We in the Square believe in resilience… in life with parole, with the possibility of time added for good behavior. 

We believe in heroes...

Tuesday, January 19, 2016

Uncertain Health in an Insecure World – 72

“White Drops of Immortality”

Many myths and religious beliefs relate to longevity. Powerful rulers, kings and pharaohs, have been obsessed with longer life and the afterlife. In East Asian mythology, the ‘elixir of life’ is brewed by a white hare on the Moon (below) – a potion that when consumed in a special cup at certain hour imbues eternal life. Alchemists in various ages and cultures have long sought such “white drops of immortality”.

But we are mere mortals, not gods or demi-gods.

And with the losses last week of David Bowie and Alan Rickman at age 69 from liver and pancreatic cancer, and yesterday of Glenn Frey at 67 from ulcerative colitis complications, we are rudely reminded of our own mortality. Global human life expectancy at birth (LEB) is currently 71 years (see post #71). David, Alan and Glenn almost made it…

The longest lived human on record, Jeanne Calment, died at an age of 122 years. In the Bible, Moses led the Exodus from Egypt at age 80, and is said to have lived 120 years.

Today, 63 years since James Watson and Francis Crick decoded DNA’s double helix, nearly 20 years since the Human Genome Project, we humans are no closer to living longer as a species.

Understanding something does not guarantee results.

Epidemiological data implicates two kinds of genetic influences on human longevity: 1) parental consanguinity (first cousins intermarrying; see map below) producing homozygous allele recessive gene expression, increasing the incidence of multifactorial traits, and 2) advanced paternal age at conception, leading to new mutations in the population.

The heritability of genes that promote longevity and healthy aging is immensely complex, and each human aging phenotype is uniquely influenced by its surrounding environment. Genome wide association studies (GWAS) have identified several interesting gene-trait longevity relationships, but none have achieved genome-wide scientific significance. In a Leiden Germany GWAS, the APO E4 gene (see post 71) has been shown to be deleterious to longevity.

The sixty-two wealthiest humans have more wealth than the poorest 3.5 billion. Many of these modern ultra-wealthy are enamored of longevity. In their remaining years, many will spend much of their personal fortunes in a scientific search for the elixir of life.

Silicon Valley has A LOT of enthusiasm for tapping into technology to restore the fountain of youth. For example, hedge funder Joon Yun (age 49) has established the Palo Alto Longevity Prize – a $1M life sciences competition dedicated to ending aging. Half of the prize money will go to scientists who can stop and then reverse human physiology in order to restore homeostasis of heart rate variability to that of a young adult. To receive the other half of ‘The Prize’, scientists will need to demonstrate an invention that extends mammalian life by 50% beyond the average for that species.

Can the code of life be hacked? Billionaires and their companies are bullish about reverse-engineering biology to extend life. 

Google’s CEO Sergei Brin (age 41) founded Calico in 2013. Calico, short for California Life Company, is a biotech with the mission of devising “interventions that enable people to lead longer and healthier lives.” With a seemingly endless bankroll of funds, Calico scientists like Cynthia Kenyon have genetically engineered roundworms that live 6-times longer than normal. Calico and pharma giant AbbVie joined forces in 2014 to pour $1.5B into anti-aging research. By comparison, the NIH’s National Institute on Aging (NIA) annually allocates $1.17B into this science of aging domain, including a special $100M budget boost for Alzheimer’s research. Brin has a gene that predisposes Parkinson’s disease, and his wife co-founded 23andMe.

Bio-technologist pioneer Craig Venter (age 68) and successful tech entrepreneur and ‘X Prize’ founder Peter Diamandis (age 54) have formed a newco called Human Longevity Inc (HLI), to develop a giant database of 1 million human genome sequences by 2020. HLI includes big data from super-centenarians who live beyond 110 years (only 1 in 1,000 of those living to 100 years). Venter envisages that HLI and Calico will join forces so, together, “it can help me live longer.”

To most humans, aging seems unavoidable.

Google’s Aubrey de Grey (age 52) is not one of them. A long-bearded maverick who serves on the Palo Alto Longevity Prize board, de Grey claims that the world is in a “pro-aging trance” that accepts the inevitability of aging as a being a medical problem. His avant-garde beliefs, such as the first person who will live to 1,000 years having already been born, make him unpopular with some mainstream anti-aging scientists. After all, the Bible states that Noah lived to 950, although God forbade life beyond 120 years after The Flood.

Aging is physiology, not illness. People without serious diseases do simply die of “old age.”

Since 2009, de Grey has been the CSO at the Strategies for Engineered Negligible Senescence (SENS) foundation, to which Silicon Valley PayPal billionaire and VC heavyweight Peter Thiel (age 47) has generously contributed. Yearly, SENS carries out $5M of anti-aging research. Several other billionaires have foundations designed to extend the human ‘health span’ – life before the frailty of aging sets in. The (Larry, age 70) Ellison Medical Foundation and the Paul (age 71) Glenn Foundation for Medical Research are two examples, where research on resilience against later lifespan extension is still occurring, despite LEB gains due to successes in childhood disease treatments and global public health. 

The genes of mice are not of men.

Despite scientific successes extending the lives of round worms and mice, the human aging condition seems resistant to change. There are now >20 mouse models of drug-induced longevity! The scientific community, skeptical a decade ago about drugs and diets extending life, has grown enthusiastic about interventions that reduce cancer risk from immune system burnout, and the deadly march of neuro-degeneration. Novartis has drugs that improve the immune response to flu vaccine by 20%. Glaxo-Smith-Kline has purchased the rights to plant-derived resveratrol that extends yeast cell and mouse lifespans, and stabilizes amyloid plaques in Alzheimer’s Disease. Stanford scientists are studying whether blood transfusion from young donors extend the lives of older recipients.

Public health policy longevity initiatives are slowly emerging.

The EU Healthy Ageing Initiative has recently established an official policy goal of extending health span by two years by 2020 as a shared societal goal! Average EU LEB for males is currently 76 years, and 82 years for females. The massive infusion of Syrian refugees make this all seem aspirational (see post #69).

The UK Human Longevity Panel has robustly debated whether evidence supports efforts to stretch human lifespans beyond 120 years, with some experts “believing that there was no limit.” Published biology supports the 12 decade hard ceiling, but enthusiasts like Craig Venter say, “I don’t see any absolute biological limit on human age.”

Like the pharaohs, modern billionaires can invest their riches in what they choose.

Scientists are honorably compelled to study prolonging the human condition.

The songs and portrayals of rockers and actors outlive their creators.

We in the Square are moved to wonderment by these modern mythologies.

And for us all, “It ain’t over ‘til the fat lady sings.” 

Until it is… 

Monday, January 11, 2016

Uncertain Health in an Insecure World – 71

“Before I Get Old”

In My Generation (1965), The Who protested that their parents were holding them back. “Hope I Die Before I Get Old” was the youthful Pete Townshend’s lament against the ravages of time. 

Pete is now 70 years old.

In their parents’ era, BBC Radio listeners heard poet Dylan Thomas’ read Do Not Go Gentle Into That Good Night. Thomas chided his father to fight on, despite the old man’s life being filled with disease and pain. “Old age should burn and rave at the close of day…Rage, Rage against the dying of the light”, even if the next day brings suffering. In the sci-fi movie Interstellar (2014), Professor John Brand (played by Michael Caine, age 82) repeated this line as the world urged NASA astronauts into the abyss of space on a vain mission to save struggling humankind.

Life expectancy at birth (LEB) is a statistic applicable to all living organisms – man, animals and plants.

LEB is an actuarial measure of an organism’s expected survival in the face of evolution, innate host defenses and lifestyle. Whether humans, opossums or guppies are involved, greater predation and accidental death lessens the impact of natural selection on increased life span.  Externally imposed caloric restriction and intrinsically lower basal metabolic rates are also known to lengthen lifespans – just ask any 190 year old Galapagos giant tortoise, or 405 year old Arctic Ocean quahog clam!

In the Bronze Age (3,000 – 1,200 B.C., left) and Iron Age (1,200 – 550 B.C., right), human LEB was just 26 years. Over thousands of intervening years, world-wide LEB doubled to 52 years for those born in 1960-65.  For the 2010-2015 birth cohort, LEB increased to 71 years. Ceteris paribus, current projections are that LEB will rise to 75 years by 2040-45. 

Doing the math, LEB gained +0.38 years per year over the prior 50 years, but will grow by only +0.13 years per year over the next 30 years. If the human genome remains largely stable, then this apparent blunting of the LEB curve (below) must be due to putative externalities – accidental deaths, predation (i.e., wars, genocides), excessive caloric intake (i.e., diabetes), and/or global environmental decline.

For rockers, life has an especially poor prognosis.

The Who drummer, Keith Moon (above), died at age 32; it was not a natural death. A 2012 British Medical Journal study sampled 1,489 rock and pop stars from 1956 and 2006, and showed that 9% died prematurely, largely as a result of substance abuse tied to psychic trauma from adverse childhood experiences (ACE).

Evolution tinkers very slowly with the human genome.

The best kept Human Genome Project (2000) secret is that differences in our genes’ DNA explain very little of why most of the lethal chronic mental and physical diseases occur – 5-10% at most!! In his January 5, 2016 blog, National Institutes of Health chief Francis Collins (age 65) reflected back on 2015’s scientific breakthroughs, highlighting the CRISPR/Cas9 gene-editing technique – Science magazine’s breakthrough of the year. “Like a scalpel”, CRISPR (below) uses an RNA segment attached to an enzyme to seek out and cut a short DNA sequence from the genome. This so-called ‘gene drive’ can re-engineer an organism’s genome, intentionally spreading a trait through a population much faster than Mendelian inheritance. Recently, Chinese scientists have used CRISPR to edit germ line cells in human embryos, edging up to the ethical red-line of engineering human life.

There are good natural selection reasons, seemingly perverse, for the preservation of mixed bag genes.

For example, the APO E4 gene located on the long arm of chromosome 19 at position 13.2 (i.e., locus 19q13.2, above) has three apolipoprotein E alleles – e2, e3 and e4 – which produce three different proteins that combine with lipids like cholesterol. More than 50% of the world’s population owns the benign ‘e3’ haplotype. But the ‘e2’version carries the risk of hyperlipoproteinemia type III, which increases the risk of atherosclerotic heart disease and stroke.  The ‘e4’ version increases the risk of late-onset Alzheimer’s disease and age-related macular degeneration.

Teleologically speaking, it could be argued that these diseases of aging are emerging now as the elderly population expands, while they were relatively rare occurrences earlier in human evolution.
Like evolution, genome-modifying research successes come slowly.

It is becoming abundantly clear that our capacity to sequence and snip genes remains a pale imitation of the natural evolution of the genome. The massive quantity of big data from genetic research initiatives continues to challenge scientists. Memorial Sloan Kettering Cancer Center’s global Project GENIE database has accrued 17,000 patient records awaiting decryption. We know that characterizing genomic mutations in tumors leads to precision medicine insights that inform clinical decision-making regarding existing drug treatment and new drug development (see Post #65). But computational challenges implicit to Project GENIE’s big datasets require big bioinformatics partners like Sage Bionetworks.

Of course, Facebook isn’t standing idly by watching the others.

At the University of Michigan, researchers have developed a Facebook app called Genes for Good, to support a genetic testing initiative that links ancestral genetic data to the daily health habits of study participants. In 2015, of the 8,310 would-be participants (below) who used the app, only 3,702 were eligible for submitting a study spit kit. Once privacy issues are managed, in 2016, the participants will receive their raw genetic data in a manageable format. Who knows what, if any, insights this information will provide to those enrolled?

In a 1989 ABC Good Morning America interview, Pete Townshend confessed that when writing the lyrics to My Generation, while riding on a train, his meaning for “old” was actually “very rich.”

There are some who believe that many nouveau riche high-tech billionaires are investing in genome manipulating precision medicine technologies to forestall their own mortality. Mark Zucherberg is 31, Travis Kalanick is 39, Sergey Brin is 42, Jeff Bezos is 51 and Bill Gates is 60.

Perhaps The Who was being prescient when Pete conflated the “old” and the “very rich”, in an era before the rise of potential LEB-adding gene-modifying technologies.

Facing it squarely, it's 2016, and we in the Square are all aging.

But before we get old, let's explore this uncharted space quadrant, and “Rage, rage against the dying of the light…”