This tells you a bit about the CEO behind the Epipen scandal. The comments were also interesting, so if you like that kind of thing, go to the site and read them.
Corporate price gouging is never nice. But gouging people on the price of medicines they rely on to stay alive is worse than not nice -- it's predaceously evil.
And if you think corporate morality can't go lower than that, how about gouging people on the price of a life-saving medicine in order to jack up the personal pay of a drug maker's CEO? That's the bottom level of grotesque immorality where Heather Bresch dwells. She is chief executive of Mylan, a pharmaceutical profiteer that markets the EpiPen medical device, which literally is a lifesaver for people who suffer deadly anaphylaxis allergy attacks.
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These allergy attacks kill nearly 200 people a year in the U.S. alone. Within seconds, something as common as peanuts or a bee sting can cause sever rash, swelling of the airways, drops in blood pressure, shock, and if not treated right away, death. So, naturally, we would want to increase access to the life-saving medicine that prevents these attacks, right?
Increasing that access is hard to do at today's price. For years, a two-shot packet of EpiPens cost under $100, but Mylan bought the rights to the injectable drug in 2007, gained monopoly control of the market, and in 2012 suddenly began sticking dependent patients again and again with drastic price hikes. Now, the two-pack averages more than $600, with some paying above $900!
Drug makers routinely claim they must charge high prices to recoup their cost of developing their products -- but Mylan didn't develop the EpiPen, taxpayers did. The original research was initiated by the Pentagon back in 1973. Today, the device and the medicine in it cost Mylan only a few dollars to produce, and the product itself is essentially unchanged from when Mylan bought it. So the company's only real contribution to the EpiPen has been to raise its price by more than 600 percent -- a shameful act of sheer profiteering that rips off hundreds of thousands of users and endangers the lives of those families who simply can't afford it.
Mylan's CEO, the one responsible for this price gouge, regards herself as a self-made corporate success story -- a woman who came out of hard-scrabble West Virginia and scrambled to the top of the food chain at Mylan. "There is a work ethic and grit about [West Virginia] that allows me to help make a difference," Bresch told the New York Times.
Well, yes, grit, hard work -- and having the advantage of being the daughter of the state's former governor and current US Senator, Joe Manchin III. Take the MBA degree she got from West Virginia University, an academic credential bestowed on her 10 years after she left the school, having completed only about half of the coursework required to get a degree. The state university later conceded that Bresch was awarded this business degree... well, because her father was governor at the time, overseeing the school's budget. It's this sort of ethical "grit" that Mylan's chief exec has employed to pick the pockets of thousands of vulnerable customers who rely on EpiPen.
Heather's greed has sparked a furious public backlash, leading to congressional investigations. But, again, her "grit" might pay off, for she has bought off several top allergy-patient advocacy groups who are not backing the people. Why? Because she's been dispensing millions of dollars to them in PR grants, making them "allies" in her blatant price-gouging scheme.
One thing that has risen higher than EpiPen's price: CEO Heather Bresch's paycheck. It's up by 671 percent since 2007, and last year alone she pocketed $18.9 million! But I wonder -- is that enough to make her feel good about being so vile? Of Course, Congress and the courts will do nothing to deter her and the other Big Pharma gougers -- but surely the lowest level of Dante's Inferno has rooms reserved for all of them.
The Point of No Return: Climate Change Nightmares Are Already Here
The worst predicted impacts of climate change are starting to happen — and much faster than climate scientists expected
Walruses, like these in Alaska, are being forced ashore in record numbers. Corey Accardo/NOAA/AP
Historians may look to 2015 as the year when shit really started hitting the fan. Some snapshots: In just the past few months, record-setting heat waves in Pakistan and India each killed more than 1,000 people. In Washington state's Olympic National Park, the rainforest caught fire for the first time in living memory. London reached 98 degrees Fahrenheit during the hottest July day ever recorded in the U.K.; The Guardian briefly had to pause its live blog of the heat wave because its computer servers overheated. In California, suffering from its worst drought in a millennium, a 50-acre brush fire swelled seventyfold in a matter of hours, jumping across the I-15 freeway during rush-hour traffic. Then, a few days later, the region was pounded by intense, virtually unheard-of summer rains. Puerto Rico is under its strictest water rationing in history as a monster El Niño forms in the tropical Pacific Ocean, shifting weather patterns worldwide.
On July 20th, James Hansen, the former NASA climatologist who brought climate change to the public's attention in the summer of 1988, issued a bombshell: He and a team of climate scientists had identified a newly important feedback mechanism off the coast of Antarctica that suggests mean sea levels could rise 10 times faster than previously predicted: 10 feet by 2065. The authors included this chilling warning: If emissions aren't cut, "We conclude that multi-meter sea-level rise would become practically unavoidable. Social disruption and economic consequences of such large sea-level rise could be devastating. It is not difficult to imagine that conflicts arising from forced migrations and economic collapse might make the planet ungovernable, threatening the fabric of civilization."
Eric Rignot, a climate scientist at NASA and the University of California-Irvine and a co-author on Hansen's study, said their new research doesn't necessarily change the worst-case scenario on sea-level rise, it just makes it much more pressing to think about and discuss, especially among world leaders. In particular, says Rignot, the new research shows a two-degree Celsius rise in global temperature — the previously agreed upon "safe" level of climate change — "would be a catastrophe for sea-level rise."
Hansen's new study also shows how complicated and unpredictable climate change can be. Even as global ocean temperatures rise to their highest levels in recorded history, some parts of the ocean, near where ice is melting exceptionally fast, are actually cooling, slowing ocean circulation currents and sending weather patterns into a frenzy. Sure enough, a persistently cold patch of ocean is starting to show up just south of Greenland, exactly where previous experimental predictions of a sudden surge of freshwater from melting ice expected it to be. Michael Mann, another prominent climate scientist, recently said of the unexpectedly sudden Atlantic slowdown, "This is yet another example of where observations suggest that climate model predictions may be too conservative when it comes to the pace at which certain aspects of climate change are proceeding."
Since storm systems and jet streams in the United States and Europe partially draw their energy from the difference in ocean temperatures, the implication of one patch of ocean cooling while the rest of the ocean warms is profound. Storms will get stronger, and sea-level rise will accelerate. Scientists like Hansen only expect extreme weather to get worse in the years to come, though Mann said it was still "unclear" whether recent severe winters on the East Coast are connected to the phenomenon.
And yet, these aren't even the most disturbing changes happening to the Earth's biosphere that climate scientists are discovering this year. For that, you have to look not at the rising sea levels but to what is actually happening within the oceans themselves.
Water temperatures this year in the North Pacific have never been this high for this long over such a large area — and it is already having a profound effect on marine life.
Related: Apocalypse Soon: 9 Terrifying Signs of Environmental Doom
Eighty-year-old Roger Thomas runs whale-watching trips out of San Francisco. On an excursion earlier this year, Thomas spotted 25 humpbacks and three blue whales. During a survey on July 4th, federal officials spotted 115 whales in a single hour near the Farallon Islands — enough to issue a boating warning. Humpbacks are occasionally seen offshore in California, but rarely so close to the coast or in such numbers. Why are they coming so close to shore? Exceptionally warm water has concentrated the krill and anchovies they feed on into a narrow band of relatively cool coastal water. The whales are having a heyday. "It's unbelievable," Thomas told a local paper. "Whales are all over the place."
Last fall, in northern Alaska, in the same part of the Arctic where Shell is planning to drill for oil, federal scientists discovered 35,000 walruses congregating on a single beach. It was the largest-ever documented "haul out" of walruses, and a sign that sea ice, their favored habitat, is becoming harder and harder to find.
Marine life is moving north, adapting in real time to the warming ocean. Great white sharks have been sighted breeding near Monterey Bay, California, the farthest north that's ever been known to occur. A blue marlin was caught last summer near Catalina Island — 1,000 miles north of its typical range. Across California, there have been sightings of non-native animals moving north, such as Mexican red crabs.
No species may be as uniquely endangered as the one most associated with the Pacific Northwest, the salmon. Every two weeks, Bill Peterson, an oceanographer and senior scientist at the National Oceanic and Atmospheric Administration's Northwest Fisheries Science Center in Oregon, takes to the sea to collect data he uses to forecast the return of salmon. What he's been seeing this year is deeply troubling.
Salmon are crucial to their coastal ecosystem like perhaps few other species on the planet. A significant portion of the nitrogen in West Coast forests has been traced back to salmon, which can travel hundreds of miles upstream to lay their eggs. The largest trees on Earth simply wouldn't exist without salmon.
But their situation is precarious. This year, officials in California are bringing salmon downstream in convoys of trucks, because river levels are too low and the temperatures too warm for them to have a reasonable chance of surviving. One species, the winter-run Chinook salmon, is at a particularly increased risk of decline in the next few years, should the warm water persist offshore.
"You talk to fishermen, and they all say: 'We've never seen anything like this before,' " says Peterson. "So when you have no experience with something like this, it gets like, 'What the hell's going on?' "
Atmospheric scientists increasingly believe that the exceptionally warm waters over the past months are the early indications of a phase shift in the Pacific Decadal Oscillation, a cyclical warming of the North Pacific that happens a few times each century. Positive phases of the PDO have been known to last for 15 to 20 years, during which global warming can increase at double the rate as during negative phases of the PDO. It also makes big El Niños, like this year's, more likely. The nature of PDO phase shifts is unpredictable — climate scientists simply haven't yet figured out precisely what's behind them and why they happen when they do. It's not a permanent change — the ocean's temperature will likely drop from these record highs, at least temporarily, some time over the next few years — but the impact on marine species will be lasting, and scientists have pointed to the PDO as a global-warming preview.
"The climate [change] models predict this gentle, slow increase in temperature," says Peterson, "but the main problem we've had for the last few years is the variability is so high. As scientists, we can't keep up with it, and neither can the animals." Peterson likens it to a boxer getting pummeled round after round: "At some point, you knock them down, and the fight is over."
Attendant with this weird wildlife behavior is a stunning drop in the number of plankton — the basis of the ocean's food chain. In July,another major study concluded that acidifying oceans are likely to have a "quite traumatic" impact on plankton diversity, with some species dying out while others flourish. As the oceans absorb carbon dioxide from the atmosphere, it's converted into carbonic acid — and the pH of seawater declines. According to lead author Stephanie Dutkiewicz of MIT, that trend means "the whole food chain is going to be different."
The Hansen study may have gotten more attention, but the Dutkiewicz study, and others like it, could have even more dire implications for our future. The rapid changes Dutkiewicz and her colleagues are observing have shocked some of their fellow scientists into thinking that yes, actually, we're heading toward the worst-case scenario. Unlike a prediction of massive sea-level rise just decades away, the warming and acidifying oceans represent a problem that seems to have kick-started a mass extinction on the same time scale.
Jacquelyn Gill is a paleoecologist at the University of Maine. She knows a lot about extinction, and her work is more relevant than ever. Essentially, she's trying to save the species that are alive right now by learning more about what killed off the ones that aren't. The ancient data she studies shows "really compelling evidence that there can be events of abrupt climate change that can happen well within human life spans. We're talking less than a decade."
For the past year or two, a persistent change in winds over the North Pacific has given rise to what meteorologists and oceanographers are calling "the blob" — a highly anomalous patch of warm water between Hawaii, Alaska and Baja California that's thrown the marine ecosystem into a tailspin. Amid warmer temperatures, plankton numbers have plummeted, and the myriad species that depend on them have migrated or seen their own numbers dwindle.
Significant northward surges of warm water have happened before, even frequently. El Niño, for example, does this on a predictable basis. But what's happening this year appears to be something new. Some climate scientists think that the wind shift is linked to the rapid decline in Arctic sea ice over the past few years, which separate research has shown makes weather patterns more likely to get stuck.
A similar shift in the behavior of the jet stream has also contributed to the California drought and severe polar vortex winters in the Northeast over the past two years. An amplified jet-stream pattern has produced an unusual doldrum off the West Coast that's persisted for most of the past 18 months. Daniel Swain, a Stanford University meteorologist, has called it the "Ridiculously Resilient Ridge" — weather patterns just aren't supposed to last this long.
What's increasingly uncontroversial among scientists is that in many ecosystems, the impacts of the current off-the-charts temperatures in the North Pacific will linger for years, or longer. The largest ocean on Earth, the Pacific is exhibiting cyclical variability to greater extremes than other ocean basins. While the North Pacific is currently the most dramatic area of change in the world's oceans, it's not alone: Globally, 2014 was a record-setting year for ocean temperatures, and 2015 is on pace to beat it soundly, boosted by the El Niño in the Pacific. Six percent of the world's reefs could disappear before the end of the decade, perhaps permanently, thanks to warming waters.
Since warmer oceans expand in volume, it's also leading to a surge in sea-level rise. One recent study showed a slowdown in Atlantic Ocean currents, perhaps linked to glacial melt from Greenland, that caused a four-inch rise in sea levels along the Northeast coast in just two years, from 2009 to 2010. To be sure, it seems like this sudden and unpredicted surge was only temporary, but scientists who studied the surge estimated it to be a 1-in-850-year event, and it's been blamed on accelerated beach erosion "almost as significant as some hurricane events."
Possibly worse than rising ocean temperatures is the acidification of the waters. Acidification has a direct effect on mollusks and other marine animals with hard outer bodies: A striking study last year showed that, along the West Coast, the shells of tiny snails are already dissolving, with as-yet-unknown consequences on the ecosystem. One of the study's authors, Nina Bednaršek, told Science magazine that the snails' shells, pitted by the acidifying ocean, resembled "cauliflower" or "sandpaper." A similarly striking study by more than a dozen of the world's top ocean scientists this July said that the current pace of increasing carbon emissions would force an "effectively irreversible" change on ocean ecosystems during this century. In as little as a decade, the study suggested, chemical changes will rise significantly above background levels in nearly half of the world's oceans.
"I used to think it was kind of hard to make things in the ocean go extinct," James Barry of the Monterey Bay Aquarium Research Institute in California told the Seattle Times in 2013. "But this change we're seeing is happening so fast it's almost instantaneous."
Thanks to the pressure we're putting on the planet's ecosystem — warming, acidification and good old-fashioned pollution — the oceans are set up for several decades of rapid change. Here's what could happen next.
The combination of excessive nutrients from agricultural runoff, abnormal wind patterns and the warming oceans is already creating seasonal dead zones in coastal regions when algae blooms suck up most of the available oxygen. The appearance of low-oxygen regions has doubled in frequency every 10 years since 1960 and should continue to grow over the coming decades at an even greater rate.
So far, dead zones have remained mostly close to the coasts, but in the 21st century, deep-ocean dead zones could become common. These low-oxygen regions could gradually expand in size — potentially thousands of miles across — which would force fish, whales, pretty much everything upward. If this were to occur, large sections of the temperate deep oceans would suffer should the oxygen-free layer grow so pronounced that it stratifies, pushing surface ocean warming into overdrive and hindering upwelling of cooler, nutrient-rich deeper water.
Enhanced evaporation from the warmer oceans will create heavier downpours, perhaps destabilizing the root systems of forests, and accelerated runoff will pour more excess nutrients into coastal areas, further enhancing dead zones. In the past year, downpours have broken records in Long Island, Phoenix, Detroit, Baltimore, Houston and Pensacola, Florida.
Evidence for the above scenario comes in large part from our best understanding of what happened 250 million years ago, during the "Great Dying," when more than 90 percent of all oceanic species perished after a pulse of carbon dioxide and methane from land-based sources began a period of profound climate change. The conditions that triggered "Great Dying" took hundreds of thousands of years to develop. But humans have been emitting carbon dioxide at a much quicker rate, so the current mass extinction only took 100 years or so to kick-start.
With all these stressors working against it, a hypoxic feedback loop could wind up destroying some of the oceans' most species-rich ecosystems within our lifetime. A recent study by Sarah Moffitt of the University of California-Davis said it could take the ocean thousands of years to recover. "Looking forward for my kid, people in the future are not going to have the same ocean that I have today," Moffitt said.
As you might expect, having tickets to the front row of a global environmental catastrophe is taking an increasingly emotional toll on scientists, and in some cases pushing them toward advocacy. Of the two dozen or so scientists I interviewed for this piece, virtually all drifted into apocalyptic language at some point.
For Simone Alin, an oceanographer focusing on ocean acidification at NOAA's Pacific Marine Environmental Laboratory in Seattle, the changes she's seeing hit close to home. The Puget Sound is a natural laboratory for the coming decades of rapid change because its waters are naturally more acidified than most of the world's marine ecosystems.
The local oyster industry here is already seeing serious impacts from acidifying waters and is going to great lengths to avoid a total collapse. Alin calls oysters, which are non-native, the canary in the coal mine for the Puget Sound: "A canary is also not native to a coal mine, but that doesn't mean it's not a good indicator of change."
Though she works on fundamental oceanic changes every day, the Dutkiewicz study on the impending large-scale changes to plankton caught her off-guard: "This was alarming to me because if the basis of the food web changes, then . . . everything could change, right?"
Alin's frank discussion of the looming oceanic apocalypse is perhaps a product of studying unfathomable change every day. But four years ago, the birth of her twins "heightened the whole issue," she says. "I was worried enough about these problems before having kids that I maybe wondered whether it was a good idea. Now, it just makes me feel crushed."
Katharine Hayhoe, a climate scientist and evangelical Christian, moved from Canada to Texas with her husband, a pastor, precisely because of its vulnerability to climate change. There, she engages with the evangelical community on science — almost as a missionary would. But she's already planning her exit strategy: "If we continue on our current pathway, Canada will be home for us long term. But the majority of people don't have an exit strategy. . . . So that's who I'm here trying to help."
James Hansen, the dean of climate scientists, retired from NASA in 2013 to become a climate activist. But for all the gloom of the report he just put his name to, Hansen is actually somewhat hopeful. That's because he knows that climate change has a straightforward solution: End fossil-fuel use as quickly as possible. If tomorrow, the leaders of the United States and China would agree to a sufficiently strong, coordinated carbon tax that's also applied to imports, the rest of the world would have no choice but to sign up. This idea has already been pitched to Congress several times, with tepid bipartisan support. Even though a carbon tax is probably a long shot, for Hansen, even the slim possibility that bold action like this might happen is enough for him to devote the rest of his life to working to achieve it. On a conference call with reporters in July, Hansen said a potential joint U.S.-China carbon tax is more important than whatever happens at the United Nations climate talks in Paris.
One group Hansen is helping is Our Children's Trust, a legal advocacy organization that's filed a number of novel challenges on behalf of minors under the idea that climate change is a violation of intergenerational equity — children, the group argues, are lawfully entitled to inherit a healthy planet.
A separate challenge to U.S. law is being brought by a former EPA scientist arguing that carbon dioxide isn't just a pollutant (which, under the Clean Air Act, can dissipate on its own), it's also a toxic substance. In general, these substances have exceptionally long life spans in the environment, cause an unreasonable risk, and therefore require remediation. In this case, remediation may involve planting vast numbers of trees or restoring wetlands to bury excess carbon underground.
Even if these novel challenges succeed, it will take years before a bend in the curve is noticeable. But maybe that's enough. When all feels lost, saving a few species will feel like a triumph.
Odds are good that the worst wildfire disaster in U.S. history might not happen in the West – but in New Jersey. Find out why.
Donald Trump's alarming speech on Thursday night was built around the claim that immigrants are a uniquely terrifying source of murder and mayhem and therefore, in the name of self-defense, the U.S. should expunge undocumented immigrants and narrow the standards for legal immigration.
The problem with his argument — which is barely an argument and more a bunch of right-wing buzzwords expectorated at top volume — is that immigrants, undocumented or not, commit crime at lower rates than native-born people.
There are, however, two groups of people who really do commit crime, especially violent crime, at wildly different rates: Men and women.
According to FBI crime statistics, men are arrested for roughly three-quarters of all crimes. When it comes to violent crime, the stats are even worse. Nearly 9 out of 10 people arrested for murder are male. Ninety-nine percent of rape arrestees are men. Men are arrested for 8 out of 10 aggravated assaults.
If Trump is right and the crime rate is serious enough of a problem to compel us to abandon basic human rights so as to subject certain groups of people to monitoring and legal intimidation, then it's not immigrants we should target. It's men.
Trump argued that all "energies of the federal government and legislative process" should be geared toward preventing immigrant-caused crime through extreme police-state measures — monitoring, draconian punishments, mass deportations, that sort of thing. The problem is that doing this won't do much to reduce crime, since immigrants aren't committing crimes in disproportionate numbers.
But if we took that police state model that Trump is suggesting and applied it to men, well, say what you will about squishy liberal values like respect for human rights and the concept of "innocent until proven guilty" and "not holding all members of a group accountable for the actions of the few," but it's hard to deny that this would significantly reduce crime.
Using Saudi Arabia, which has really perfected gender apartheid, as an inspiration, I have crafted a 10-point plan, aimed at controlling men, that Trump should embrace if he's really serious about preventing crime at all costs.
1. Chaperoning. No man is allowed to leave the house, even on simple errands, without a female relative to chaperone him. It can be his wife, sister, mother or even sister-in-law, so long as there is proper documentation to show that this woman has the authority to mind him while he's out. It's hard to rape and murder people with your mom watching you.
2. A driving ban. We know that male criminals frequently use cars to escape a crime scene, and in some cases, like drunken-driving accidents (which men cause at twice the rate for women), the vehicle is the instrument of the crime. Given men too much accelarating power makes it too easy for men to indulge their criminal urges. They can either get a ride from a woman or take the bus.
3. Guardianship. Men shouldn't be able to get jobs, go to school or leave the country without the permission of their female guardian. This precaution will keep them from socializing with other men who are unknown by their female guardian, as this activity is a known precursor to criminal activity. Men will be banned from leadership positions as well because they can't be trusted to deal fairly and strictly with their fellow males who commit crime.
4. A ban on nonmarital sex. Men commit nearly all rapes, but they often get away with it because they simply claim that the sex was consensual. Banning nonmarital sex solves most of the he-said, she-said problem. Men will definitely be motivated to make sure a woman doesn't feel violated by a sexual encounter, if she can get him 40 lashes with an accusation of fornication.
This ban, like all bans on this list, will be for men only. Women have proved they are more responsible, by committing less crime, and can be trusted to make their own decisions.
5. Modest clothing. Under the new law, men will be required to wear heavy robes that cover everything but their hands and face. They will don head coverings so that no one can see hair or a bald spot. It is very hard to rape someone if you have to spend an hour removing your clothing. It's also hard to flee from a crime scene if you're tripping over your robes. Most important, making men look ridiculous will discourage their showing off for their bros, which leads to all sorts of criminal mischief, from vandalism to bar fights.
As a side benefit, this will rid the world of cargo shorts, aviator sunglasses and backward baseball caps.
6. A ban on congregating in public. During his speech, Trump railed about how "the gangs are all over the place." Most gang members are not immigrants, but most of them are male. Under the new law, all-female police forces will roam the streets, making sure that any group of men larger than three individuals is dispersed immediately to prevent the formation of gangs.
7. A ban on bank accounts. Money is the reason men commit a lot of crimes. If they can't have any of their own, that should dampen their enthusiasm for stealing.
8. A ban on drinking alcohol. Male consumption of alcohol is a factor in a whole mess of crimes, especially rape. From here on out, only women will be allowed to drink. Married men will be allowed one glass of wine at dinner, if their wives allow it.
9. A ban on overly masculine pop culture. There are entire swaths of pop culture that only men really seem to like and this probably means that these art forms contribute to crime. As a precaution, they will be banned.
Rap rock, dubstep and Rush records will be the first to go.
On the highbrow end, all independent dramas that feature a young man falling in love with a girl who is beautiful but too broken to marry will be banned, and their screenwriters sentenced to a life of hard labor. If "daddy issues" are a major theme in these dramas, a board of female censors will screen these movies to determine if they are too boring for them to allow them to go into wide release.
Anything made by Zack Snyder will be burned.
Computers full of pornographic anime will be seized and destroyed.
Owning those "V for Vendetta" masks will result in a minimum five-year sentence.
"My Little Pony" will be allowed for little girls, but grown men engaging with its fictional universe in any way will be put in a harness and made to pull a carriage around the park for a year.
With inspiration from this year's "Ghostbusters" release, all Hollywood remakes of classic films will star majority-female casts.
10. A ban on social media. For years, women have had to endure harassment from men on Facebook, Twitter and Snapchat and now from heaven only knows what other social-media app that's popped up lately. And everyone throws their hands in the air and says there's nothing we can really do about it.
False! If you ban men from social media, you can cut back on the vast majority of the harassment. Having a Twitter, Facebook or other social-media account will land a man a year in prison. Using any of these services to send a dick pic will get him 10 years. Going on Reddit will result in having a hand cut off.
If you've gotten this far in the piece, congratulations. My proposal may sound tough, but tough times call for tough measures. I am the law-and-order journalist. Trump should immediately drop his anti-immigration plan and adopt this plan that's guaranteed to lower the crime rate.
Amanda Marcotte is a politics writer for Salon. She's on Twitter @AmandaMarcotte.
This is really exciting. Let's hope it works and is safe! It could cure Alzheimer's, Parkinson's and maybe mad cow disease too! well-written article too. (Mad Cow disease is the one the author calls Creutzfeldt-Jakob disease, in case you didn't know -- it's really scary. )
In 2004, the British chemist Chris Dobson speculated that there might be a universal elixir out there that could combat not just alpha-synuclein for Parkinson's but the amyloids caused by many protein-misfolding diseases at once. Remarkably, in that same year an Israeli scientist named Beka Solomon discovered an unlikely candidate for this elixir, a naturally occurring microorganism called a phage.
Solomon, a professor at Tel Aviv University, made a serendipitous discovery one day when she was testing a new class of agents against Alzheimer's disease. If it pans out, it might mark the beginning of the end of Alzheimer's, Parkinson's, and many other neurodegenerative diseases. It's a remarkable story, and the main character isn't Solomon or any other scientist but a humble virus that scientists refer to as M13.
Alzheimer's disease can cause brain tissues to atrophy, seen here in blue.
Among the many varieties of viruses, there is a kind that only infects bacteria. Known as bacteriophages, or just phages, these microbes are ancient (over three billion years old) and ubiquitous: they're found everywhere from the ocean floor to human stomachs. The phage M13's goal is to infect just one type of bacteria,Escherichia coli, or E. coli, which can be found in copious amounts in the intestines of mammals. Like other microorganisms, phages such as M13 have only one purpose: to pass on their genes. In order to do this, they have developed weapons to enable them to invade, take over, and even kill their bacterial hosts. Before the advent of antibiotics, in fact, doctors occasionally used phages to fight otherwise incurable bacterial infections.
To understand Solomon's interest in M13 requires a little background about her research. Solomon is a leading Alzheimer's researcher, renowned for pioneering so-called immunotherapy treatments for the disease. Immunotherapy employs specially made antibodies, rather than small molecule drugs, to target the disease's plaques and tangles. As high school students learn in biology class, antibodies are Y-shaped proteins that are part of the body's natural defense against infection. These proteins are designed to latch onto invaders and hold them so that they can be destroyed by the immune system. But since the 1970s, molecular biologists have been able to genetically engineer human-made antibodies, fashioned to attack undesirable interlopers like cancer cells. In the 1990s, Solomon set out to prove that such engineered antibodies could be effective in attacking amyloid-beta plaques in Alzheimer's as well.
In 2004, she was running an experiment on a group of mice that had been genetically engineered to develop Alzheimer's disease plaques in their brains. She wanted to see if human-made antibodies delivered through the animals' nasal passages would penetrate the blood-brain barrier and dissolve the amyloid-beta plaques in their brains. Seeking a way to get more antibodies into the brain, she decided to attach them to M13 phages in the hope that the two acting in concert would better penetrate the blood-brain barrier, dissolve more of the plaques, and improve the symptoms in the mice—as measured by their ability to run mazes and perform similar tasks.
Solomon divided the rodents into three groups. She gave the antibody to one group. The second group got the phage-antibody combination, which she hoped would have an enhanced effect in dissolving the plaques. And as a scientific control, the third group received the plain phage M13.
Because M13 cannot infect any organism except E. coli, she expected that the control group of mice would get absolutely no benefit from the phage. But, surprisingly, the phage by itself proved highly effective at dissolving amyloid-beta plaques and in laboratory tests improved the cognition and sense of smell of the mice. She repeated the experiment again and again, and the same thing happened. "The mice showed very nice recovery of their cognitive function," Solomon says. And when Solomon and her team examined the brains of the mice, the plaques had been largely dissolved. She ran the experiment for a year and found that the phage-treated mice had 80% fewer plaques than untreated ones. Solomon had no clear idea how a simple phage could dissolve Alzheimer's plaques, but given even a remote chance that she had stumbled across something important, she decided to patent M13's therapeutic properties for the University of Tel Aviv. According to her son Jonathan, she even "joked about launching a new company around the phage called NeuroPhage. But she wasn't really serious about it."
The following year, Jonathan Solomon—who'd just completed more than a decade in Israel's special forces, during which time he got a BS in physics and an MS in electrical engineering—traveled to Boston to enroll at the Harvard Business School. While he studied for his MBA, Jonathan kept thinking about the phage his mother had investigated and its potential to treat terrible diseases like Alzheimer's. At Harvard, he met many brilliant would-be entrepreneurs, including the Swiss-educated Hampus Hillerstrom, who, after studying at the University of St. Gallen near Zurich, had worked for a European biotech venture capital firm called HealthCap.
Following the first year of business school, both students won summer internships: Solomon at the medical device manufacturer Medtronic and Hillerstrom at the pharmaceutical giant AstraZeneca. But as Hillerstrom recalls, they returned to Harvard wanting more: "We had both spent…I would call them 'weird summers' in large companies, and we said to each other, 'Well, we have to do something more dynamic and more interesting.' "
In their second year of the MBA, Solomon and Hillerstrom took a class together in which students were tasked with creating a new company on paper. The class, Solomon says, "was called a field study, and the idea was you explore a technology or a new business idea by yourself while being mentored by a Harvard Business School professor. So, I raised the idea with Hampus of starting a new company around the M13 phage as a class project. At the end of that semester, we developed a mini business plan. And we got on so well that we decided that it was worth a shot to do this for real."
In 2007, with $150,000 in seed money contributed by family members, a new venture, NeuroPhage Pharmaceuticals, was born. After negotiating a license with the University of Tel Aviv to explore M13's therapeutic properties, Solomon and Hillerstrom reached out to investors willing to bet on M13's potential therapeutic powers. By January 2008, they had raised over $7 million and started hiring staff.
Their first employee—NeuroPhage's chief scientific officer—was Richard Fisher, a veteran of five biotech start-ups. Fisher recalls feeling unconvinced when he first heard about the miraculous phage. "But the way it's been in my life is that it's really all about the people, and so first I met Jonathan and Hampus and I really liked them. And I thought that within a year or so we could probably figure out if it was an artifact or whether there was something really to it, but I was extremely skeptical."
Fisher set out to repeat Beka Solomon's mouse experiments and found that with some difficulty he was able to show the M13 phage dissolved amyloid-beta plaques when the phage was delivered through the rodents' nasal passages. Over the next two years, Fisher and his colleagues then discovered something totally unexpected: that the humble M13 virus could also dissolve other amyloid aggregates—the tau tangles found in Alzheimer's and also the amyloid plaques associated with other diseases, including alpha-synuclein (Parkinson's), huntingtin (Huntington's disease), and superoxide dismutase (amyotrophic lateral sclerosis). The phage even worked against the amyloids in prion diseases (a class that includes Creutzfeldt-Jakob disease). Fisher and his colleagues demonstrated this first in test tubes and then in a series of animal experiments. Astonishingly, the simple M13 virus appeared in principle to possess the properties of a "pan therapy," a universal elixir of the kind the chemist Chris Dobson had imagined.
This phage's unique capacity to attack multiple targets attracted new investors in a second round of financing in 2010. Solomon recalls feeling a mix of exuberance and doubt: "We had something interesting that attacks multiple targets, and that was exciting. On the other hand, we had no idea how the phage worked."
The Key
That wasn't their only problem. Their therapeutic product, a live virus, it turned out, was very difficult to manufacture. It was also not clear how sufficient quantities of viral particles could be delivered to human beings. The methods used in animal experiments—inhaled through the nose or injected directly into the brain—were unacceptable, so the best option available appeared to be a so-called intrathecal injection into the spinal canal. As Hillerstrom says, "It was similar to an epidural; this was the route we had decided to deliver our virus with."
While Solomon and Hillerstrom worried about finding an acceptable route of administration, Fisher spent long hours trying to figure out the phage's underlying mechanism of action. "Why would a phage do this to amyloid fibers? And we really didn't have a very good idea, except that under an electron microscope the phage looked a lot like an amyloid fiber; it had the same dimensions."
Boston is a town with enormous scientific resources. Less than a mile away from NeuroPhage's offices was MIT, a world center of science and technology. In 2010, Fisher recruited Rajaraman Krishnan—an Indian postdoctoral student working in an MIT laboratory devoted to protein misfolding—to investigate the M13 puzzle. Krishnan says he was immediately intrigued. The young scientist set about developing some new biochemical tools to investigate how the virus worked and also devoured the scientific literature about phages. It turned out that scientists knew quite a lot about the lowly M13 phage. Virologists had even created libraries of mutant forms of M13. By running a series of experiments to test which mutants bound to the amyloid and which ones didn't, Krishnan was able to figure out that the phage's special abilities involved a set of proteins displayed on the tip of the virus, called GP3. "We tested the different variants for examples of phages with or without tip proteins, and we found that every time we messed around with the tip proteins, it lowered the phage's ability to attach to amyloids," Krishnan says.
Virologists, it turned out, had also visualized the phage's structure using X-ray crystallography and nuclear magnetic resonance imaging. Based on this analysis, those microbiologists had predicted that the phage's normal mode of operation in nature was to deploy the tip proteins as molecular keys; the keys in effect enabled the parasite to "unlock" E. coli bacteria and inject its DNA. Sometime in 2011, Krishnan became convinced that the phage was doing something similar when it bound to toxic amyloid aggregates. The secret of the phage's extraordinary powers, he surmised, lay entirely in the GP3 protein.
As Fisher notes, this is serendipitous. Just by "sheer luck, M13's keys not only unlock E. coli; they also work on clumps of misfolded proteins." The odds of this happening by chance, Fisher says, are very small. "Viruses have exquisite specificity in their molecular mechanisms, because they're competing with each other…and you need to have everything right, and the two locks need to work exactly the way they are designed. And this one way of getting into bacteria also works for binding to the amyloid plaques that cause many chronic diseases of our day."
Having proved the virus's secret lay in a few proteins at the tip, Fisher, Krishnan, and their colleagues wondered if they could capture the phage's amyloid-busting power in a more patient friendly medicine that did not have to be delivered by epidural. So over the next two years, NeuroPhage's scientists engineered a new antibody (a so-called fusion protein because it is made up of genetic material from different sources) that displayed the critical GP3 protein on its surface so that, like the phage, it could dissolve amyloid plaques. Fisher hoped this novel manufactured product would stick to toxic aggregates just like the phage.
By 2013, NeuroPhage's researchers had tested the new compound, which they called NPT088, in test tubes and in animals, including nonhuman primates. It performed spectacularly, simultaneously targeting multiple misfolded proteins such as amyloid beta, tau, and alpha-synuclein at various stages of amyloid assembly. According to Fisher, NPT088 didn't stick to normally folded individual proteins; it left normal alpha-synuclein alone. It stuck only to misfolded proteins, not just dissolving them directly, but also blocking their prion-like transmission from cell to cell: "It targets small aggregates, those oligomers, which some scientists consider to be toxic. And it targets amyloid fibers that form aggregates. But it doesn't stick to normally folded individual proteins." And as a bonus, it could be delivered by intravenous infusion.
The Trials
There was a buzz of excitement in the air when I visited NeuroPhage's offices in Cambridge, Massachusetts, in the summer of 2014. The 18 staff, including Solomon, Hillerstrom, Fisher, and Krishnan, were hopeful that their new discovery, which they called the general amyloid interaction motif, or GAIM, platform, might change history. A decade after his mother had made her serendipitous discovery, Jonathan Solomon was finalizing a plan to get the product into the clinic. As Solomon says, "We now potentially have a drug that does everything that the phage could do, which can be delivered systemically and is easy to manufacture."
Will it work in humans? While NPT088, being made up of large molecules, is relatively poor at penetrating the blood-brain barrier, the medicine persists in the body for several weeks, and so Fisher estimates that over time enough gets into the brain to effectively take out plaques. The concept is that this antibody could be administered to patients once or twice a month by intravenous infusion for as long as necessary.
NeuroPhage must now navigate the FDA's regulatory system and demonstrate that its product is safe and effective. So far, NPT088 has proved safe in nonhuman primates. But the big test will be the phase 1A trial expected to be under way this year. This first human study proposed is a single-dose trial to look for any adverse effects in healthy volunteers. If all goes well, NeuroPhage will launch a phase 1B study involving some 50 patients with Alzheimer's to demonstrate proof of the drug's activity. Patients will have their brains imaged at the start to determine the amount of amyloid-beta and tau. Then, after taking the drug for six months, they will be reimaged to see if the drug has reduced the aggregates below the baseline.
To learn more about ongoing Alzheimer's clinical trials, watch "Can Alzheimer's Be Stopped?" streaming online.
"If our drug works, we will see it working in this trial," Hillerstrom says. "And then we may be able to go straight to phase 2 trials for both Alzheimer's and Parkinson's." There is as yet no imaging test for alpha-synuclein, but because their drug simultaneously lowers amyloid-beta, tau, and alpha-synuclein levels in animals, a successful phase 1B test in Alzheimer's may be acceptable to the FDA. "In mice, the same drug lowers amyloid beta, tau, and alpha-synuclein," Hillerstrom says. "Therefore, we can say if we can reduce in humans the tau and amyloid-beta, then based on the animal data, we can expect to see a reduction in humans in alpha-synuclein as well."
Along the way, the company will have to prove its GAIM system is superior to the competition. Currently, there are several drug and biotech companies testing products in clinical trials for Alzheimer's disease, against both amyloid-beta (Lilly, Pfizer, Novartis, and Genentech) and tau (TauRx) and also corporations with products against alpha-synuclein for Parkinson's disease (AFFiRiS and Prothena/Roche). But Solomon and Hillerstrom think they have two advantages: multi-target flexibility (their product is the only one that can target multiple amyloids at once) and potency (they believe that NPT088 eliminates more toxic aggregates than their competitors' products). Potency is a big issue. PET imaging has shown that existing Alzheimer's drugs like crenezumab reduce amyloid loads only modestly, by around 10%. "One weakness of existing products," Solomon says, "is that they tend to only prevent new aggregates. You need a product potent enough to dissolve existing aggregates as well. You need a potent product because there's a lot of pathology in the brain and a relatively short space of time in which to treat it."
Future Targets
NeuroPhage's rise is an extraordinary example of scientific entrepreneurship. While I am rooting for Solomon, Hillerstrom, and their colleagues, and would be happy to volunteer for one of their trials (I was diagnosed with Parkinson's in 2011), there are still many reasons why NeuroPhage has a challenging road ahead. Biotech is a brutally risky business. At the end of the day, NPT088 may prove unsafe. And it may still not be potent enough. Even if NPT088 significantly reduces amyloid beta, tau, and alpha-synuclein, it's possible that this may not lead to measurable clinical benefits in human patients, as it has done in animal models.
But if it works, then, according to Solomon, this medicine will indeed change the world: "A single compound that effectively treats Alzheimer's and Parkinson's could be a twenty billion-dollar-a-year blockbuster drug." And in the future, a modified version might also work for Huntington's, ALS, prion diseases like Creutzfeldt-Jakob disease, and more.
I asked Jonathan about his mother, who launched this remarkable story in 2004. According to him, she has gone on to other things. "My mother, Beka Solomon, remains a true scientist. Having made the exciting scientific discovery, she was happy to leave the less interesting stuff—the engineering and marketing things for bringing it to the clinic—to us. She is off looking for the next big discovery."
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