Wednesday, November 30, 2016

Uncertain Health in an Insecure World – 99

“Fecal Matters”

Humans are made up of 50% somatic cells and 50% microbes!

Long before next-generation gene sequencing (NGS) technology, using a simple little device (the compound microscope), Dutchman Antonie van Leewenhoek (1632-1723; below) showed that the body’s oral and fecal bacterial populations were very different. 

Van Leewenhoek, the “father of microbiology”, also proved that the microbial flora he called ‘animalcules’ (below) differed between healthy and diseased humans.

The insight that healthy humans coexist with bacteria and other bugs in a “microbiota” won Joshua Lederberg (1925-2008; below) the 1958 Nobel Prize for Medicine & Physiology. Lederberg and his colleagues showed that bacteria can mate and exchange genes (i.e., bacterial conjunction). 

At just 33 years of age, the new Nobel Laureate went west to found the Department of Genetics at Stanford University. In the 1950’s he and Carl Sagan raised concerns about the biological effects of space travel, advising NASA to isolate returning astronauts and sterilize equipment to prevent extraterrestrial microbes from contaminating to Earth. In the 1960’s he worked with Stanford Computer Science Department chair, Edward Feigenbaum, to develop the first artificial intelligence platform, DENDRAL (a portmanteau of dendritic algorithm).

And in 2001, Dr. Lederberg coined the term “human microbiome.”

Since 2008, the U.S. National Institutes of Health Human Microbiome Project (HMP) has been characterizing the distribution and genomics of the microbial communities found at multiple body sites, to determine whether and how changes in the human microbiome impact health. In conjunction with other members of the international Human Microbiome Consortium, the HMP used NGS to characterize 3,000 genomes from bacteria, viruses and protozoans (below). 

These projects generated a human metagenomic big data repository for comparing microbes to the human cells with which they co-exist (below). The 5-year US$115M HMP has studied the sharing of common microbe-cell metabolic pathways and the exchange of genomic material, in both healthy symbiotic and disease-producing states.

In June 2016, the Obama Administration launched the follow-on US$121M Microbiome Initiative. Like the Precision Medicine Initiative (PMI) and the Cancer Moonshot, it’s unclear if this program will be part of the Obama legacy, or be euthanized by the new Donald Trump Administration.

Fun Fact – the newest effective human transplant material is feces.

Yes… you heard correctly!

Doctors can obtain fresh stool from healthy donors to replenish the normal gut bacteria of patients with recurrent Clostridium difficile (C. diff.; above) infections. C. diff. toxin causes colonic inflammation and chronic diarrhea. Annually, in the U.S. C. diff. infects between 640,000 and 820,000 Americans, killing 14,000. Fecal microbial transplant (FMT, a.k.a. “bacteriotherapy”) was shown to be more effective than oral vancomycin therapy in preventing further infections in a study of 16 Dutch patients with recurrent C. diff. colitis (New Eng. J. Med. 368: 407-415, 2013).

Not surprisingly, FMT patients have a preference for related donors.

To address the problem of potentially lethal hospital-acquired C. diff. infections and the FMT “ick factor”, doctors at Canada’s Kingston General Hospital and the University of Western Ontario have now developed a 33 gut bacterial species of “pseudo-poo” that serves as a stool substitute, precluding the need for fecal material infusion. The lead doctors, Elaine Petrof and Gregory Gloor, like to think of the mixture a rectally administered yogurt! Microbial cocktails are now being tested in patients with inflammatory bowel disease (IBD; Nature Biotechnology 33:787-788, 2015). 

Investigators from the University of Ottawa have reported significant differences in the metagenomics of gut microbes in children with two genetically similar IBD's – Crohn’s Disease and ulcerative colitis (UC). They have also shown that the microbial dysbiosis of Crohn’s disease is associated with down-regulation of mitochondrial proteins that detoxify H2S, and that Atopobium parvulum is the network controller of other H2S-producing pro-inflammatory gut microbes (Nature Communications, 7: 13419, 2016).

In the last few years, recognition of the immunomodulatory effects of the human microbiome has led start-ups and Big Pharma to seek out novel therapies.

Boston-based Vendanta Biosciences has been working on a “bug drugs” since 2012, backed by private equity funds from PureTech Ventures. In 2015, they announced the successful development of a 17 C. diff. strain called VE202. This VE202 cocktail is thought to push out the bad C. diff. bugs by rejuvenating T-reg lymphocyte immune functions, thereby reducing gut inflammation. In January 2015, the Janssen Biotech division of Johnson & Johnson (JNJ) Pharmaceuticals licensed this novel technology from Vendanta for an initial fee of US$241M. The Jansen Human Microbiome Institute (JHMI), established in Cambridge MA in 2014, is intensively plumbing microbiome therapeutics with numerous partners. The head of JNJ Innovation at the JHMI, Anuk Das (below), believes that this pipeline will be effective in autoimmune, inflammatory and infectious diseases.

Seres Therapeutics (NASDAQ:MCRB) became the first company in the human microbiome sector to go public. Backed by Flagship Ventures, Seres began as a 2010 Cambridge MA start-up. Their June 2015 IPO netted US$139M ($18 per share), based on the promising results of phase-1 clinical trials with SER-109 (Nature Biotechnology 33: 787-788, 2015). SER-109 (ECOSPOR™) is a carefully controlled mix of 50 bacterial spores obtained from healthy donors. Although FDA-designated as a “breakthrough therapy,” in July 2016 Seres announced that SER-109 “unexpectedly” failed to meet its goal in a phase-2 clinical trial – it did not reduce the relative risk of C. diff. recurrence compared to placebo. Not unexpectedly, MCRB share prices tumbled 75% from $35.77 to $8.74 per share. 

Of course, Seres has other drugs in the pipeline. For example, SER-262 is a synthetically-derived microbiome modifying agent for C. diff. infection now in phase-1b trials. Seres’ other EcobioticR drugs are entering phase-1b studies for treating patients with inflammatory diseases like Crohn’s, UC and non-insulin dependent type-2 diabetes.

Among the many emerging companies attracting Pharma and VC attention in the human microbiome therapeutics space are Enterome, Second Genome, EpiBiome and uBiome.

The World Health Organization reports 1.7 billion global cases of diarrheal disease per year, with 760,000 deaths per year in children under the age of 5 years. The primary associations of this potentially lethal illness are malnutrition, poor sanitation and contaminated drinking water. While this disease is far more of a global public health risk, Pharma and VC will follow Sutton’s Law, focusing their funds on the developed world’s perceived needs for new technologies and drugs for C. diff., UC or Crohn’s disease.

We in the Square don’t pooh-pooh these fast emerging human microbiome innovations. 

But we loudly lament a market reality that sees “the others” impatiently waiting for the constipated global diffusion of such benefits.

Thursday, November 17, 2016

Uncertain Health in an Insecure World – 98

“Best and Worst of Times”

In every era, writers portray the reality of modern life through fiction. Charles Dickens (1812-1870) did this in his sweeping novels, giving the world and subsequent generations a glimpse into mid-19th century Victorian Britain. Anton Chekhov (1860-1904) wrote plays and short stories that were social commentaries and sharp critiques of a feudal Romanov Russia. No strangers to pathos and irony, their protagonists and bit players written lives reflected their times.

So too has it been this year, in most dramatic fashion.

In June, the 52% pro-Brexit referendum vote transformed the face of European immigration, trade, law, science and business. Bloodless exits, whether “soft” or “hard”, create and kill many jobs, and change millions of lives.

Last week, with just 47% of the presidential vote, Donald J. Trump transformed the U.S. electoral map and the ground rules of American politics.

These two surprising events were not simply about change.

While wildly unpredictable, by and through the will of The People, these events became binding upon their governments.

While peaceful, through neither war nor coup d’ ├ętat, the outcomes are being described as revolutionary.

While the leaders and forces at work differed in many ways, these sentinel events grew out of popular movements, whether reasoned or misguided.

And while these two jurisdictions operate different democracies, the administrative course of the related policy, regulatory and procedural sequelae will massively impact their governments for decades.

Historians relate these two eruptions to pent up emotions – people longing to feel “great again” – pining for the gilded eras of The British Empire and broad-shouldered American Determinism. In those days these two countries were indeed “great”, uniquely projecting their military might and commercial power across the known world.

But now the globe is flat, and nine countries have deployed nuclear weapons (above).

Britain and America were victors in two World Wars, and allies against aggression, totalitarianism and genocide. Their post-Nazi refugee scientists ushered in the atomic age, discovered new drugs & vaccines, and pierced Earth’s atmosphere.

But since those good old days, and absent a 21st century cataclysm – a world war, revolution, depression or nuclear detonation – to wipe the slate clean, incremental innovation begins to feel… well, unsatisfying.

Transformation – peaceful or otherwise – is a much more potent stimulus to the masses, especially when incrementalism feels like two steps forward, one step back. Transformation can also be framed as a rallying cry against a common enemy.

But when the adrenaline rush ends, and real change crashes back to Earth, it falls to the least innovative and most risk-averse among us – the bureaucrats – to plod the path forward and quietly attend to their chores.

Absent a pressing political or military upheaval, the masses have wed an easily adopted and widely accessible mate – hand held technology. Statista projects there will be 4.8B humans using mobile phones in 2017! What is the first thing you do in the morning? Tell the truth…

The constant, unfiltered, seductive whir of social media was the Enigma machine of Brexit and Trump-ism.

Not to be confused with New York’s CA Technologies that powered CNN’s fail fast election analytics, Cambridge Analytica (above) crunched big data into “psychographic" profiles of voters for both of these winning campaigns. Cambridge Analytica is a U.S. subsidiary of the British behavioral research firm SCL Group Ltd. that worked with the Leavers in the Brexit vote. The company is partly funded by Robert Mercer (below), the computer scientist co-CEO of the secretive quant hedge fund, Renaissance Technologies.

In the months leading up to the final U.S. presidential vote, Cambridge Analytica also crunched Donald Trump’s numbers and by the election eve, their models predicted a 50% chance of victory when CNN's poll of polls had him down 4-6%. While political pundits and other predictive models were blowing it BIG at the BBC and CNN, Trump’s 3 AM tweets were winning hearts and bending minds. While Hillary’s email words were being redacted and refuted, spin machines and influencers were dashing her hopes & dreams and converting his big data into votes.

Cambridge Analytica’s motto, “We know what you want before you want it…” is both clever and chilling.

Whether dreaming of walls or glass ceilings, or having nightmares about terrorists or refugees, in the deep dark recesses of voters’ brains something began resonating.

Neuroscience can always explain what we humans do, but it cannot defend it. 

The neo-cortex is the unique home of human creativity and intellect. Great literature evokes a higher consciousness. Dickens makes us sad, and Chekhov brings us to tears.

But the hind brain is the deep seat of behavioral psychology. Before conscious thought occurs, fearful cues trigger fight or flight reflexes. We remain or leave. Such Pavlovian stimuli make us drool…

The edgy rant of Chicago-based blogger David Wong (below and at, who ripped Clinton voters for ignoring years of blue collar suffering and decline in rural America, now rings true – “Are you assholes listening now?

We in the city Square can now hear the “Others” voices.

And we all need to listen more carefully going forward. 

Tuesday, November 8, 2016

Uncertain Health in an Insecure World – 97

“Whatever… Wherever”

In 1956, the United States legally changed its official motto from “E pluribus unum” to “In God We Trust.”

Sixty years hence, as the 2016 U.S. Presidential Election results roll in, we will learn whether the “wherever” misogynist Donald Trump or the lyin’ “whatever” Hillary Clinton will become the leader of The Free World. Regardless of the outcome, the future of American Healthcare is at best uncertain and at worst unsustainable.

No subject has been studied so deeply, yet so stubbornly defiant of a solution.

Why is that?

Healthcare, prescription drugs, elder care and child care sectors are all characterized by rapidly rising prices and limited technological innovation.

Venture capitalist and Netscape founder Marc Andreessen (above) recently opined (Oct. 5, 2016>new-money>2016/10) about a “technology bust” in the healthcare and life sciences sectors, which have historically demonstrated inflexibility to change. He cited market inelasticity for innovations that would increase productivity or reduce costs. According to Andreessen, these sectors suffer from “dysfunctional behaviors that lead to rapid increases in prices… monopolies, oligopolies, cartels, government-run markets, price fixing.” He added, when “government injects more subsidies into those inelastic markets… (they) cause prices to go up further.

He’s totally right!

There are no other markets like healthcare and Pharma. 
Andreessen believes that Theranos’ 2016 collapse occurred as a result of a “beta release as production” business strategy that may only work in Silicon Valley. But the blood-testing start-up failed fast, never impressing either Wall Street or the U.S. Centers for Medicare & Medicaid Services (CMS). Theranos CEO Elizabeth Holmes (below) has laid off 340 workers, and the company plans to close all of its clinical labs. Now Theranos is being sued by one of its original hedge fund investors, Partner Fund Management (PFM).

The private equity bubble that created highly valued unicorns like Uber, Airbnb, Snapchat and Theranos has not produced typical initial public offerings (IPO’s). Instead, it has spurred big money late round investing by hedge funds (like PFM) and institutional investors (like Fidelity). Typically, the pre-IPO / pre-acquisition VC vetting process is much more robust, and is better suited to the nature of these increasingly rare exits.

As politics inevitably creep in, the U.S. healthcare sector is irreparably harmed.

According to Harvard Business School (HBS) Baker Foundation Professor Leonard Schesinger, after the “fall and fix” of Obamacare’s website, the situation has gone from bad to worse ( Cold Call Podcast Oct. 20, 2016). Variable state-by-state interpretations of the Affordable Care Act (ACA) have been bungled because the creation of state insurance exchanges requires complex managerial tasks.

As gleefully pointed out by the Trump campaign, the opting out of many insurance carriers and the depleted numbers of ‘healthy’ enrollees has ballooned Obamacare health insurance premiums for those trying to comply with ACA mandates (above). Many young people faced with >US$500 per month premium bills are just opting out, instead taking the much lower Internal Revenue Service penalty charge on their federal taxes.

HBS case studies describe the adverse outcomes associated with the multiplayer accountability gaps of Obamacare and the failure to adopt open innovation at NASA (‘Houston we Have a Problem’, May 5, 2014, Both have suffered from the same quasi-governmental “Who’s on first?” confusion. The private sector players see the blood in the water, swooping in with standard management tools or hyperbolic IT solutions, while securing nicely leveraged financial positions.

Increasingly, Fintech approaches may be a key to overdue solutions for healthcare malaise.

The average ATM transaction is $60. The average hospital transaction is $1,600. The Smart Card Alliance reports that 140 million smart cards have now been issued by hospitals around the world to identify patients, instead of using paper-based demographic and personal information validation.

Governments have repeatedly tried to foster innovation to hold down healthcare prices, without taking any market risk. They recognize that the price problem is largely due to insufficient technology adoption. But despite penalties and incentives, the healthcare system holds out and holds on. Such slavish orthopraxy is resulting in continuing delays in the adoption of ‘meaningful use’ of the electronic health record (EHR) required by the Obamacare law.

The U.S. healthcare industrial complex increasingly controls the data. This dis-intermediates doctors from patients.

Widespread unhappiness with EHR technology has created unlikely bedfellows – consumer and health IT advocates – to push for more personal health record keeping. The 3rd phase of Obamacare policy meaningful use requires that EHR vendors certify that they use open application programming interfaces (API’s) for exchanging EHR’s. In response, Epic, Cerner and Allscripts announced that their API’s would employ the Fast Health Interoperability Resources (FHIR) standard and be open. Ideally, these changes will allow greater user access to their PHI.

According to health guru Eric Topol (tri-cording Stephen Colbert, below), access to our personal health information (PHI) will become a human rights issue in coming years.

Now that would indeed be disruptive innovation!!

Of interest, Dr. Topol’s Scripps Translational Science Institute recently received a $20M federal Precision Medicine Initiative grant, and also signed a partnership agreement with Apple. POLITICO reports ( ) that Apple is moving into healthcare, including FDA-regulated sensors, clinical decision support, and EHR’s. Apple-philes hope that the company will make patients the guardians of their own health data. When patients can download their PHI onto iPhones via a platform of API’s, the smartphone could emerge as the middleman in healthcare.

The reason that Healthcare is economic kryptonite to the globe’s greatest superpower is simple.

In its uniquely manifest destiny mindset, America has rejected the complete overhaul of its public-private quasi-market healthcare system because it’s simply too big to concede failure.

Whether in politics or business, changing a president or CEO is not transformation.

Deeply entrenched dysfunctions of bureaucracy and management will survive the peaceful transfer of power that follows the U.S. Presidential Election on January 20, 2017.

Brexit and this damn election have damaged Trust.

So, by God, we in the Square suggest resurrecting, “Out of many, one…”