Even for the nonsqueamish and otherwise healthy, a blood test can be a fraught event. Is my cholesterol too high? Are my organs functioning properly? Are these results going to change my life? If a group of heavyweight scientists and pharma executives working out of a 10th Street office park succeeds, a new layer could be added to that physical and emotional calculus: concrete biological evidence of your risk for suicide, PTSD, depression, and a host of other mental health conditions.
MindX Sciences, an Indianapolis-based biotech startup, is pitching a product that deals with the mind and body as one. Its app tracks psychological symptoms through a simple questionnaire and then, crucially, combines that data with a revolutionary blood test that its scientists say can reliably—and objectively—detect risk for mental health disorders. Its data is then used to tailor treatment to a patient’s specific needs, in a fashion that would go far beyond what MindX says is the current “19th-century” status quo in psychiatry.
The idea almost seems implausible: How can the complexities of the mind be reduced to a set of numbers printed off the DeskJet in your physician’s back office? Psychiatry is based on skilled, professional interpretations of what are still ultimately subjective descriptions by patients of their feelings. What drives one person to bed with depression for a weekend might drive someone else to a much darker place. Philosophers have wrestled for centuries with what they call the “mind-body problem,” the struggle to identify the point where our biology meets the sui generis emotions and experiences that make up our interior lives. How far can a mere blood test go toward demystifying a problem that has eluded thinkers for almost as long as humans have been able to, well, think?
According to Dr. Alexander Niculescu—the Indiana University psychiatrist and geneticist who cofounded the company, serves as its chairman and CEO, and developed the pathbreaking blood test at the product’s heart—it could cover a pretty fair distance.
“I’m not going to veer toward the philosophical side of things, but biology underpins everything that we do,” Niculescu says. “If you have that view, that’s a constructive, or optimistic, or positive view, because then there’s something you can do about things when they don’t work well.”
The “things” in question here are the chemicals in our brains that signal us to depression or anxiety or PTSD, driven by our emotions and detected by Niculescu’s test in our very DNA. Imagine, for example, a patient reporting intense bouts of restless sleep, a loss of appetite, and inability to concentrate. Their physician draws their blood and, using MindX’s test, finds one of the markers of severe depression, enabling them to begin treatment with a higher level of speed and accuracy than traditional psychiatric assessment would provide. It’s a bold idea, but he and others in the field say that the identification of such “biomarkers” in the blood—the genetic expressions that reveal the presence of mental health issues—will supplement, not supplant, traditional psychiatric practice.
“Psychiatrists need tools,” says Dr. Zachary Kaminsky, an epigeneticist at the Royal Ottawa Mental Health Centre in Canada, a research hospital in Ottawa, Ontario. Kaminsky, whose research focuses on biologically detecting suicide risk, came across Niculescu’s research when they each individually discovered the same biomarker for it. “I think that these tools have the potential to be transformative,” he says.
That promise has led to a wave of coverage for MindX in both the scientific and mainstream press when it launched in 2019, reaching even national outlets including ABC News. But contrary to the future-shock hype that inevitably surrounds such a revolutionary product, Niculescu, whose devotion to scientific empiricism outstrips even his considerable ambition, has honed the technology at its heart over more than a decade. And the fact that MindX’s board includes veterans of such industry heavy hitters as Phillips, Eli Lilly, and Bayer, implies there could be more to his discovery beyond just a few promising studies.
MindX’s app is available now through Apple’s App Store, and its president Sunil Hazaray says the company is negotiating with hospitals in Indianapolis, California, and the United Kingdom who are interested in a trial program for its blood test. His goal is that in five years, the MindX test will be available in 15 to 20 percent of America’s hospitals. But a product as cutting-edge as MindX claims theirs to be is bound to have skeptics, not least in the cutthroat world of venture capital, where they’ll need to prove it’s viable both medically and as a money-maker. The rubber is about to meet the road for Niculescu’s promised mental health revolution. What remains to be seen is whether patients, physicians, and investors are ready to buy in.
Even via Zoom, Niculescu cuts an imposing figure. Romanian-born, he has long, drawn features and an accent that now carries a trace of clipped Midwestern-ness from his nearly two decades at Indiana University. Having spent the decade prior on the West Coast, where he completed a Ph.D. and post-doctoral residency at Scripps Research in La Jolla, California, he has seen the difference between breathless startup hype and the evidence-based revolution that MindX promises.
“The ‘fake it till you make it’ approach they take in Silicon Valley… you know, maybe it plays well in software, but it doesn’t play well in medicine, where you’re dealing with people’s lives,” Niculescu says. “I’ve been here 15 years, so I’m sort of an adoptive Midwesterner, and we tend to be more circumspect.”
Despite his circumspection, Niculescu’s academic pedigree spans the modern history of biology and genetics. At Scripps, he completed his post-doctorate with Gerald Edelman, the Nobel Prize–winning biologist who identified the molecular structure of antibodies. After conquering that frontier, Edelman turned his attention to the brain, proposing a series of ambitious and controversial theories about human cognition. His 1992 book Bright Air, Brilliant Fire explored the concept of “Neural Darwinism,” describing in detail the way the brain builds consciousness through a series of links at the molecular level of which only the strongest and most resilient survive (hence its name).
One of the most prominent critics of that theory, and one of Edelman’s lifelong rivals, was Francis Crick, the legendary molecular biologist who codiscovered DNA’s double helix. Soon after his time with Edelman, Niculescu found himself working side by side with Crick, a relentless empiricist whose more sober approach is reflected in Niculescu’s eagerness to demystify the heady philosophical questions that his product invites.
“He would take me to the faculty club once a month for lunch, and I would pour out my enthusiasm and crazy ideas, and he would nudge me in one way or the other,” Niculescu says.
Niculescu’s Scripps Ph.D. was in molecular biology, focusing on the genetics of cancer. But after working closely with trailblazers like Crick and Edelman, he says he felt called to dedicate his career to exploring something that still eludes our full scientific understanding—the mind. Put another way, one could say that cancer was too easy.
“There was a lot of work to be done, but there were no mysteries left,” Niculescu says. “I thought, what do I want to do the next 30 or 40 years of my life? Do I want to be an oncology doctor and cancer researcher, or do I want to go into the brain, which is the ultimate frontier?”
Niculescu’s work is part of a long scientific tradition, taking tools that have already proven successful in one field—the genetic analysis he brings to bear on mental health is commonly used in the world of cancer research—and using them to break new ground in another. Kaminsky, his fellow researcher, describes the challenges they both face.
“I’ve taken a look at the literature lately to see if there’s a lot more momentum in the space,” Kaminsky says. “I’m not sure if there is because these types of studies are hard.”
Alan Schatzberg, a Stanford psychiatrist and former president of the American Psychiatric Association, has studied depression for decades. He’s seen countless efforts to track its genetics come and go, generating hype and promise but precious little results.
“These biomarkers, they’ve been quite elusive,” Schatzberg says. “Most psychiatric disorders are not Mendelian,” referring to the earliest-identified and simplest form of genetic inheritance. “They’re all complex genetics, made up of small genes, or the small effects of many genes, and that makes diagnostic tests that much more difficult.”
The hereditary inheritance Schatzberg refers to is the idea that a trait present in an organism, whether a pea plant or a human being, is reflective of one gene’s dominance over another—a binary switch being flipped that makes your hair brown or your eyes blue or a tulip yellow. For the presence of depression, schizophrenia, or any number of other psychiatric disorders, it’s nowhere near that simple to identify.
“Most medical disorders have developed tests that are highly sensitive and highly specific,” Schatzberg adds. “In psychiatry, compared to other fields of medicine, they are not terribly sensitive or terribly specific. Nobody has come up with one or two that really are highly effective. It’s a tricky business.”
Niculescu claims to have solved this problem, finding the “needle in a haystack,” as he describes it, by bringing a technical approach to bear that’s unique in the field of mental health. His approach is not to find a single gene that might predict or reflect mental health disorders, but to find patterns of genetic expression in the blood that can be matched consistently to mental distress. Reflecting the doctor’s own eclectic background, the idea is borrowed from the world of cancer research, where such “liquid biopsies” are used commonly to find DNA from cancer cells in the blood.
Niculescu’s path to finding consistent biological markers for mental health has four steps. First, subjects are tracked and tested as part of lengthy longitudinal studies over the course of several years, which allows Niculescu and his team to observe them in both highly symptomatic and nonsymptomatic states. This is a crucial break from the norm in medical research. Typically, researchers will seek the largest sample size possible in order to reduce potential “noise” in the data, that is, when outlier results are over-represented due to a small sample size. That poses problems for genetic research into mental health, where expression of a disorder can be both highly complex and highly inconsistent—leading to a whole lot of “noise.”
Niculescu believes smaller cohorts, observed closely over a long period of time, can lead to results that are just as reproducible as those from larger cohorts. He cites research from Stanford molecular geneticist Michael Snyder, who found reliable predictors of diabetes in a sample size of just one person—Snyder himself. Niculescu says Snyder’s paper showing his work was a major step toward demonstrating the power of small sample sizes.
Once Niculescu and his team of researchers have followed a cohort for long enough to determine a set of likely biomarkers, the second step is to compare them against the existing body of data from other researchers, in a manner Niculescu compares to Google’s page-ranking algorithm. Third, once they’ve settled on the strongest candidates for those biomarkers, they test them against an independent cohort of a “clinically sick” population that is currently presenting with extreme mental health symptoms. Finally, researchers take the biomarkers that have survived those three rounds of testing and apply them to an additional independent clinical group to see if they predict the severity of their mental health conditions, as well as a need for future hospitalizations.
So far, the approach has been promising. Over the past decade, Niculescu has published major studies on biomarkers for suicide risk, pain, PTSD, and memory issues and Alzheimer’s disease. In 2017, Niculescu published a study in the scientific journal Molecular Psychiatry that combined the results of MindX’s blood test and responses to a questionnaire within its mobile apps to predict an increase in thoughts of suicide with 90 percent accuracy in independent cohorts. The test also predicted with 77 percent accuracy which subjects would eventually require hospitalization due to suicide risk.
But suicide, although one of the most urgent and extreme symptoms of mental health concerns, poses a series of issues in its study. For one, it’s difficult to measure for obvious logistical reasons. Niculescu and his researchers have a partnership with the Marion County Coroner’s office where they collect blood samples from people who have completed suicide within 24 hours or less, using the data to validate their biomarkers. And thorny issues around privacy and confidentiality cast an even darker shadow over the research: After the 2017 study, one patient committed suicide.
When Niculescu’s research group found out, they reviewed the patient’s data, which revealed she was at extremely high risk. But because she was part of the anonymized research study, they had no way to identify that patient and warn her doctors. Niculescu credits the experience as an inspiration behind starting MindX, the better to put the company’s tools into practice and prevent such incidents in the future.
Still, Niculescu and Hazaray also acknowledge that suicide can be, frankly, a hard sell. They say the company has shifted its approach in recent months from an early focus on their success identifying suicide risk to pitching it as an all-purpose preventative product—the better to both broaden its appeal to hospitals and identify mental health symptoms before they lead to suicidal ideation down the road. Their pivot reveals how Niculescu’s scientific breakthrough may be a massive achievement, but convincing hospitals and investors to buy in might be another in its own right.
Teri Willey is the executive director of IU Ventures, the university’s venture fund that invests in IU-affiliated startups and innovations. She says that in addition to making for a slow, careful research process, Niculescu and MindX’s ambition may be the very thing that makes such a company a challenge to market.
“With any early-stage company, especially one that’s [IU] faculty-bounded, usually the science is excellent, and the unmet need is clear,” Willey says. “Whether it can be a business or not is usually the most difficult thing to determine.”
Lori LeRoy is the executive vice president of communications for BioCrossroads, a company that promotes and facilitates collaboration within Indiana’s biotech scene. She has worked in the industry for most of her career and has seen how products with even obvious home-run potential can get bogged down, tripped up, or otherwise relegated to “what if” status.
“Clinical trials cost tens of millions of dollars to do, to make sure things are safe and efficacious,” LeRoy says. “It’s a long road for these guys.”
From a sales and product standpoint, MindX’s own “what if” is tantalizing: The company pitches itself as providing a comprehensive framework for treating mental health that goes beyond just its all-important blood test, with the combined results from its app and that test enabling hyperindividualized treatment for each patient. They call it “precision medicine for the mind.”
“At first people didn’t understand that these apps were not just sort of another app. These are science-driven, clinically validated apps that measure something that is relevant clinically,” Niculescu says. “It didn’t help us with investors at first. People asked, ‘Are you an app company, are you a software company, what are you?’”
To fine-tune Niculescu’s vision, MindX has brought on industry veterans like the company’s president Sunil Hazaray, a former vice president of molecular diagnostics at Roche and president and CEO of Bayer subsidiary Viterion. MetLife and Vertex Pharmaceuticals board member Diana McKenzie is an investor, and among its cofounders are several biotech entrepreneurs with decades of startup experience among them.
The company’s seed money came from Don Brown, the Indianapolis-based serial investor and CEO of LifeOmic, a health software company that shares an address with MindX at IU’s Emerging Technologies Center on 10th Street. (The original CEO and president of MindX was local venture capitalist Matthew Neff; both Neff and Niculescu declined to comment on his departure.)
From an investment standpoint, the names on a startup’s resume, so to speak, can be as important as the science itself, if not more so.
“What matters to us is that you’ve got a team that you think can execute against the business plan,” says Willey. “It’s that you understand what the risks are. Things will never work out exactly as you think they’re going to when you present that business plan and that business model, so is this a group that has the wherewithal to see the warning signs early?”
“The name-brand, high-level executives are mindful of where they are spending their time and energy,” says Ting Gootee, chief investment officer for local firm Elevate Ventures. “You really have to do a good job of telling them why this is a worthwhile opportunity.”
In the life sciences sector, Indiana has more than its share of such name-brand bigwigs for Niculescu and his team to pick off.
“We have strengths in pharmaceuticals, biotech, pharmaceutical development, medical devices, diagnostics, and ag-biosciences,” says Patty Martin, BioCrossroads’s president and CEO. “This differentiates Indiana from the coasts, where, generally, they are often strong in just one or two sectors of the life sciences.”
Hazaray says the company hopes by the middle of 2021 to reach Series A funding (a first round of venture capital for companies that have proven promising but need additional cash). He says the company’s biggest challenge so far has been going through the arduous process of FDA approval.
Kaminsky, the Canadian epigeneticist, agrees that the sheer newness of a product like MindX serves as the most significant roadblock for such companies, especially given its unique approach to the science.
“It’s early,” Kaminsky says. “It’s harder for technologies that not everyone is doing, and so sometimes you have to do it yourself … maybe that’s why they’ve created their own startup to do this instead of going with a licensing model, I don’t know. But I know that from meeting Dr. Niculescu he seems like a person who’s passionate about helping people, and he believes in his work. That’s probably why he’s doing it himself.”
To that point, when asked about why the world might be more ready to take a chance on his technology than it was at the turn of the last decade, Niculescu becomes especially animated when talking about something that couldn’t be farther from the molecular precision of a blood test: the messy, uncomfortable social dynamics surrounding mental illness.
“The stigma part was an issue years ago, but it’s less of an issue now,” Niculescu says. “It depends on the geographic area, the socioeconomic background, the cultural background, and so on, but across all those different divides. People are more open. They see that celebrities have bipolar disorder, depression, commit suicide, and so on. That’s immensely helpful to patients because they feel it’s not a weakness or something that they need to deal with by themselves or be ashamed of.”
Although our collective understanding of mental health issues has grown from both a scientific and social perspective, leaders in the field know that one misstep can send public opinion flying back in the opposite direction. Teri Willey says that might require MindX to take as counterintuitive an approach to its business as Niculescu did with his science.
“It’s a really important space for investment, and so getting it right will be really important because you don’t want there to be a backlash if things are brought to use that don’t perform as expected,” Willey says. “You have to be not just innovative with your approach to therapy, but innovative with business models, too.”
“We’ve had more disappointments than other fields of medicine,” Schatzberg says. “Even if we had a [reliable mental health biomarker] test, I’m not sure you could be able to sell it to people, users or regulators, that in fact this is really helpful or effective.”
Niculescu has made proving that wrong his life’s work. The idea at the heart of his pitch is undoubtedly radical—if not to entirely demystify, then to map the undiscovered country of one’s mind, the better to traverse it with care and caution. But as audacious as that concept is, the process of making it real has been somewhat quotidian, filled with the backtracking endemic to scientific discovery.
“Dr. Niculescu has done a good job of being an empiricist,” Kaminsky says. “That’s a good approach, to be skeptical of your own work, and then only carry forward that which survives the true test.”
Another “true test,” of course, is the marketplace. Based on what Niculescu has heard from patients, he’s confident that there’s demand.
“I work with veterans,” Niculescu says. “These guys come in banged up from Iraq, Afghanistan, and so on, they have PTSD, and they say, ‘Doc, we would love for there to be a blood test …to show that what’s happening isn’t just my weakness, it’s not just something in my mind, it’s something objective that’s happening in my body, in my brain.’”
Which, of course, is exactly what MindX’s product purports to do. And if it works as intended, the “mind-body problem” may be ultimately less a weighty philosophical question than a simple IT problem.
“If you look at a computer, you have hardware and software, and the two are intricately connected,” Niculescu says. “How we feel and think is a sort of software that runs on this hardware, and they’re very hard to extricate. You can’t run the software in some ethereal fashion without having the machine to run the hardware. I don’t view it as something very mysterious.”