Elizabeth Holmes Through the Director’s Lens
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.
"The Inventor," a chronicle of Theranos's storied downfall, premiered recently on HBO. Leapsmag reached out to director Alex Gibney, whom The New York Times has called "one of America's most successful and prolific documentary filmmakers," for his perspective on Elizabeth Holmes and the world she inhabited.
Do you think Elizabeth Holmes was a charismatic sociopath from the start — or is she someone who had good intentions, over-promised, and began the lies to keep her business afloat, a "fake it till you make it" entrepreneur like Thomas Edison?
I'm not qualified to say if EH was or is a sociopath. I don't think she started Theranos as a scam whose only purpose was to make money. If she had done so, she surely would have taken more money for herself along the way. I do think that she had good intentions and that she, as you say, "began the lies to keep her business afloat." ([Reporter John] Carreyrou's book points out that those lies began early.) I think that the Edison comparison is instructive for a lot of reasons.
First, Edison was the original "fake-it-till-you-make-it" entrepreneur. That puts this kind of behavior in the mainstream of American business. By saying that, I am NOT endorsing the ethic, just the opposite. As one Enron executive mused about the mendacity there, "Was it fraud or was it bad marketing?" That gives you a sense of how baked-in the "fake it" sensibility is.
"Having a thirst for fame and a noble cause enabled her to think it was OK to lie in service of those goals."
I think EH shares one other thing with Edison, which is a huge ego coupled with a talent for storytelling as long as she is the heroic, larger-than-life main character. It's interesting that EH calls her initial device "Edison." Edison was the world's most famous "inventor," both because of the devices that came out of his shop and and for his ability for "self-invention." As Randall Stross notes in "The Wizard of Menlo Park," he was the first celebrity businessman. In addition to her "good intentions," EH was certainly motivated by fame and glory and many of her lies were in service to those goals.
Having a thirst for fame and a noble cause enabled her to think it was OK to lie in service of those goals. That doesn't excuse the lies. But those noble goals may have allowed EH to excuse them for herself or, more perniciously, to make believe that they weren't lies at all. This is where we get into scary psychological territory.
But rather than thinking of it as freakish, I think it's more productive to think of it as an exaggeration of the way we all lie to others and to ourselves. That's the point of including the Dan Ariely experiment with the dice. In that experiment, most of the subjects cheated more when they thought they were doing it for a good cause. Even more disturbing, that "good cause" allowed them to lie much more effectively because they had come to believe they weren't doing anything wrong. As it turns out, economics isn't a rational practice; it's the practice of rationalizing.
Where EH and Edison differ is that Edison had a firm grip on reality. He knew he could find a way to make the incandescent lightbulb work. There is no evidence that EH was close to making her "Edison" work. But rather than face reality (and possibly adjust her goals) she pretended that her dream was real. That kind of "over-promising" or "bold vision" is one thing when you are making a prototype in the lab. It's a far more serious matter when you are using a deeply flawed system on real patients. EH can tell herself that she had to do that (Walgreens was ready to walk away if she hadn't "gone live") or else Theranos would have run out of money.
But look at the calculation she made: she thought it was worth putting lives at risk in order to make her dream come true. Now we're getting into the realm of the sociopath. But my experience leads me to believe that -- as in the case of the Milgram experiment -- most people don't do terrible things right away, they come to crimes gradually as they become more comfortable with bigger and bigger rationalizations. At Theranos, the more valuable the company became, the bigger grew the lies.
The two whistleblowers come across as courageous heroes, going up against the powerful and intimidating company. The contrast between their youth and lack of power and the old elite backers of Theronos is staggering, and yet justice triumphed. Were the whistleblowers hesitant or afraid to appear in the film, or were they eager to share their stories?
By the time I got to them, they were willing and eager to tell their stories, once I convinced them that I would honor their testimony. In the case of Erika and Tyler, they were nudged to participate by John Carreyrou, in whom they had enormous trust.
"It's simply crazy that no one demanded to see an objective demonstration of the magic box."
Why do you think so many elite veterans of politics and venture capitalism succumbed to Holmes' narrative in the first place, without checking into the details of its technology or financials?
The reasons are all in the film. First, Channing Robertson and many of the old men on her board were clearly charmed by her and maybe attracted to her. They may have rationalized their attraction by convincing themselves it was for a good cause! Second, as Dan Ariely tells us, we all respond to stories -- more than graphs and data -- because they stir us emotionally. EH was a great storyteller. Third, the story of her as a female inventor and entrepreneur in male-dominated Silicon Valley is a tale that they wanted to invest in.
There may have been other factors. EH was very clever about the way she put together an ensemble of credibility. How could Channing Robertson, George Shultz, Henry Kissinger and Jim Mattis all be wrong? And when Walgreens put the Wellness Centers in stores, investors like Rupert Murdoch assumed that Walgreens must have done its due diligence. But they hadn't!
It's simply crazy that no one demanded to see an objective demonstration of the magic box. But that blind faith, as it turns out, is more a part of capitalism than we have been taught.
Do you think that Roger Parloff deserves any blame for the glowing Fortune story on Theranos, since he appears in the film to blame himself? Or was he just one more victim of Theranos's fraud?
He put her on the cover of Fortune so he deserves some blame for the fraud. He still blames himself. That willingness to hold himself to account shows how seriously he takes the job of a journalist. Unlike Elizabeth, Roger has the honesty and moral integrity to admit that he made a mistake. He owned up to it and published a mea culpa. That said, Roger was also a victim because Elizabeth lied to him.
Do you think investors in Silicon Valley, with their FOMO attitudes and deep pockets, are vulnerable to making the same mistake again with a shiny new startup, or has this saga been a sober reminder to do their due diligence first?
Many of the mistakes made with Theranos were the same mistakes made with Enron. We must learn to recognize that we are, by nature, trusting souls. Knowing that should lead us to a guiding slogan: "trust but verify."
The irony of Holmes dancing to "I Can't Touch This" is almost too perfect. How did you find that footage?
It was leaked to us.
"Elizabeth Holmes is now famous for her fraud. Who better to host the re-boot of 'The Apprentice.'"
Holmes is facing up to 20 years in prison for federal fraud charges, but Vanity Fair recently reported that she is seeking redemption, taking meetings with filmmakers for a possible documentary to share her "real" story. What do you think will become of Holmes in the long run?
It's usually a mistake to handicap a trial. My guess is that she will be convicted and do some prison time. But maybe she can convince jurors -- the way she convinced journalists, her board, and her investors -- that, on account of her noble intentions, she deserves to be found not guilty. "Somewhere, over the rainbow…"
After the trial, and possibly prison, I'm sure that EH will use her supporters (like Tim Draper) to find a way to use the virtual currency of her celebrity to rebrand herself and launch something new. Fitzgerald famously said that "there are no second acts in American lives." That may be the stupidest thing he ever said.
Donald Trump failed at virtually every business he ever embarked on. But he became a celebrity for being a fake businessman and used that celebrity -- and phony expertise -- to become president of the United States. Elizabeth Holmes is now famous for her fraud. Who better to host the re-boot of "The Apprentice." And then?
"You Can't Touch This!"
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.
Podcast: The Friday Five Weekly Roundup in Health Research
The Friday Five covers five stories in research that you may have missed this week. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on scientific creativity and progress to give you a therapeutic dose of inspiration headed into the weekend.
Here are the promising studies covered in this week's Friday Five:
- Not a fan of breathing in micro plastics? New robot noses could help
- You don't need a near-death experience to get the benefits
- How to tell the difference between good and bad inflammation
- Brain shocks for better memory - don't try this at home (yet)!
- A new way to know if your bum back is getting better
The honorable mention for this week's Friday Five: One activity can increase your longevity even without good genes for living longer.
Schizophrenia is a debilitating mental health condition that affects around 24 million people worldwide. Patients experience hallucinations and delusions when they develop schizophrenia, with experts referring to these new thoughts and behaviors as positive symptoms. They also suffer from negative symptoms in which they lose important functions, suffering from dulled emotions, lack of purpose and social withdrawal.
Currently available drugs can control only a portion of these symptoms but, on August 8th, Karuna Therapeutics announced its completion of a phase 3 clinical trial that found a new drug called KarXT could treat both positive and negative symptoms of schizophrenia. It could mean substantial progress against a problem that has stymied scientists for decades.
A long-standing problem
Since the 1950s, antipsychotics have been used to treat schizophrenia. People who suffer from it are thought to have too much of a brain chemical called dopamine, and antipsychotics work by blocking dopamine receptors in the brain. They can be effective in treating positive symptoms but have little impact on the negative ones, which can be devastating for a patient’s quality of life, making it difficult to maintain employment and have successful relationships. About 30 percent of schizophrenia patients don't actually respond to antipsychotics at all. Current drugs can also have adverse side effects including elevated cholesterol, high blood pressure, diabetes and movements that patients cannot control.
The recent clinical trial heralds a new treatment approach. “We believe it marks an important advancement for patients given its new and completely different mechanism of action from current therapies,” says Andrew Miller, COO of Karuna.
Scientists have been looking to develop alternatives. However, “the field of drug treatment of schizophrenia is currently in the doldrums,” says Peter McKenna, a senior researcher at FIDMAG Research Foundation in Spain which specialises in mental health.
In the 2000s there was a major push to target a brain receptor for a chemical called glutamate. Evidence suggested that this receptor is abnormal in the brains of schizophrenia patients, but attempts to try glutamate failed in clinical trials.
After that, many pharmaceutical companies dropped out of the race for a more useful treatment. But some companies continued to search, such as Karuna Therapeutics, led by founder and Chief Operating Officer Andrew Miller and CEO Steve Paul. The recent clinical trial suggests their persistence has led to an important breakthrough with their drug, KarXT. “We believe it marks an important advancement for patients given its new and completely different mechanism of action from current therapies,” Miller says.
How it works
Neurotransmitters are chemical messengers that pass signals between neurons. To work effectively, neurotransmitters need a receptor to bind to. A neurotransmitter called acetylcholine seems to be especially important in schizophrenia. It interacts with sites called muscarinic receptors, which are involved in the network of nerves that calm your body after a stressful event. Post mortem studies in people with schizophrenia have shown that two muscarinic receptors in the brain, the M1 and M4 receptors, are activated at unusually low levels because they don’t receive enough signals from acetylcholine.
The M4 receptor appears to play a role in psychosis. The M1 receptor is also associated with psychosis but is primarily thought to be involved in cognition. KarXT, taken orally, works by activating both of these receptors to signal properly. It is this twofold action that seems to explain its effectiveness. “[The drug’s] design enables the preferential stimulation of these muscarinic receptors in the brain,” Miller says.
How it developed
It all started in the early 1990s when Paul was at pharmaceutical company Eli Lilly. He discovered that Xanomeline, the drug they were testing on Alzheimer's patients, had antipsychotic effects. It worked by stimulating M1 and M4 receptors, so he and his colleagues decided to test Xanomeline on schizophrenia patients, supported by research on the connection between muscarinic receptors and psychosis. They found that Xanomeline reduced both positive and negative symptoms.
Unfortunately, it also caused significant side effects. The problem was that stimulating the M1 and M4 receptors in the brain also stimulated muscarinic receptors in the body that led to severe vomiting, diarrhea and even the temporary loss of consciousness.
In the end, Eli Lilly discontinued the clinical trials for the drug, but Miller set up Karuna Therapeutics to develop a solution. “I was determined to find a way to harness the therapeutic benefit demonstrated in studies of Xanomeline, while eliminating side effects that limited its development,” Miller says.
He analysed over 7,000 possible ways of mixing Xanomeline with other agents before settling on KarXT. It combines Xanomeline with a drug called Trospium Chloride, which blocks muscarinic receptors in the body – taking care of the side effects such as vomiting – but leaves them unblocked in the brain. Paul was so excited by Miller’s progress that he joined Karuna after leaving Eli Lilly and founding two previous startups.
“It's a very important approach,” says Rick Adams, Future Leaders Fellow in the Institute of Cognitive Neuroscience and Centre for Medical Image Computing at University College London. “We are in desperate need of alternative drug targets and this target is one of the best. There are other alternative targets, but not many are as close to being successful as the muscarinic receptor drug.”
Clinical Trial
Following a successful phase 2 clinical trial in 2019, the most recent trial involved 126 patients who were given KarXT, and 126 who were given a placebo. Compared to the placebo, patients taking KarXT had a significant 9.6 point reduction in the positive and negative syndrome scale (PANSS), the standard for rating schizophrenic symptoms.
KarXT also led to statistically significant declines in positive and negative symptoms compared to the placebo. “The results suggest that KarXT could be a potentially game-changing option in the management of both positive and negative symptoms of schizophrenia,” Miller says.
Robert McCutcheon, a psychiatrist and neuroscientist at Oxford University, is optimistic about the side effects but highlights the need for more safety trials.
McKenna, the researcher at FIDMAG Foundation, agrees about the drug’s potential. “The new [phase 3] study is positive,” he says. “It is reassuring that one is not dealing with a drug that works in one trial and then inexplicably fails in the next one.”
Robert McCutcheon, a psychiatrist and neuroscientist at Oxford University, said the drug is an unprecedented step forward. “KarXT is one of the first drugs with a novel mechanism of action to show promise in clinical trials.”
Even though the drug blocks muscarine receptors in the body, some patients still suffered from adverse side effects like vomiting, dizziness and diarrhea. But in general, these effects were mild to moderate, especially compared to dopamine-blocking antipsychotics or Xanomeline on its own.
McCutcheon is optimistic about the side effects but highlights the need for more safety trials. “The trial results suggest that gastrointestinal side effects appear to be manageable,” he says. “We know, however, from previous antipsychotic drugs that the full picture regarding the extent of side effects can sometimes take longer to become apparent to clinicians and patients. Careful ongoing assessment during a longer period of treatment will therefore be important.”
The Future
The team is currently conducting three other trials to evaluate the efficacy and long-term safety of KarXT. Their goal is to receive FDA approval next year.
Karuna is also conducting trials to evaluate the effectiveness of KarXT in treating psychosis in patients suffering from Alzheimer’s.
The big hope is that they will soon be able to provide a radically different drug to help many patients with schizophrenia. “We are another step closer to potentially providing the first new class of medicine in more than 50 years to the millions of people worldwide living with schizophrenia,” says Miller.