In November 2013, more than 100 patients with cancer - including pancreatic, breast, liver and brain tumours - embarked on clinical trials involving BPM 31510, a drug discovered by an algorithm.

The story of BPM 31510 begins with the extraction of biological data from healthy and cancerous tissue samples from over 1,000 patients. This data was then processed by artificial intelligence algorithms, which analysed it and suggested possible drug treatments. "We've essentially reversed the scientific method," says Niven R Narain, the 38-year-old president and co-founder of Berg, the Boston pharma startup which makes BPM 31510. "Instead of a preconceived hypothesis that leads us to do experiments and generate a particular type of data, we allowed the biological data from the patients to lead us to the hypotheses."

Making an effective cancer-fighting drug is a notoriously difficult process: according to Narain, development and production can cost pharmaceutical companies up to $2.6 billion (£1.8bn) and take 12 to 14 years to complete. "Only one per cent of the cancer drugs that make it to clinical trials prove to be effective. It's expensive and the development process is inexcusably long," Narain says. "In any other industry we would all be fired."


To Narain, the problem lies with the method used by pharmaceutical companies to produce cancer-fighting drugs. "A scientist comes up with a hypothesis that, say, a certain deviant protein is responsible for a particular type of cancer," he says. "The pharma company then tests this hypothesis

by screening the protein target against millions of compounds, looking for the few that might react chemically and potentially become a drug." This is a textbook description of the scientific method. It's a procedure that Narain describes as "hit-and-miss", a dartboard approach to curing the disease. He believes he can do better in half the time and spend less than half the money by thinking differently.

Niven R Narain is the president and co-founder of Berg Benedict Evans

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BPM 31510, a compound made with an enzyme that plays a key role in cellular metabolism, was the first treatment suggested by Berg's AI. The development of the drug effectively began back in 2009, when the startup bought cancer tissue samples from more than 1,000 cancer patients at various medical schools from across the US. These samples included over 40 types of cancer cells - multiple types of breast cancer, prostate cancer, liver cancer, kidney cancer, lung cancer, brain cancer - along with healthy tissue extracted from the same patients.

Narain didn't want to narrow down his study to just one cancer. Instead, he wanted to build a model that looked at the commonalities between the different cancers. From these samples, Berg researchers created in-vitro cell cultures that they could subject to further experimentation. To mimic the micro-environments that cells experience inside the human body, they subjected the cells in Petri dishes to different levels of sugar and oxygen and tracked their evolution by continuously identifying and measuring the lipids, metabolites, proteins and enzymes they produced. "We were measuring how the data was changing with the environment," Narain says. "Besides the genomic information, we had 14 trillion data points coming out

from one single tissue sample."


This torrent of biological data helped Berg scientists to map out the cascade of molecular reactions that occur in cells - from genes to proteins to lipids and metabolites - in unprecedented detail. Using artificial intelligence, they then compared the data between the healthy cells and the diseased cells. "It would be impossible to [manually] process all that data, or even understand it from a logical point of view," Narain says. "You need to use AI to find how normal cellular processes break down, how that leads to disease and what the potential treatments are. Most people say, 'This is not how drugs are developed.' My answer to that is: 'Exactly, because this is the way drugs should be developed'."

Niven R Narain first came to the conclusion that hypothesis-driven science was flawed when he was a 25-year-old cancer researcher at the University of Miami's Miller School of Medicine. On July 22, 2003, he performed an experiment with melanoma cells in Petri dishes. He treated them with a cream containing CoQ10, an enzyme that resides inside mitochondria, the energy source of cells. To his surprise, by the next day almost all the cancer cells in the Petri dishes were dead. He later repeated the experiment on mice with melanoma. After 30 days, the tumours had shrunk by an average of 55 per cent. Narain had no idea why this was happening.

"This was two years after the completion of the Human Genome Project," Narain says. "At the time there was a belief that cancer was primarily driven by genes. Most people believed that, after the sequencing of the genome, all we had to do was find the genes responsible for cancer, modulate them, and cure most cancers." Narain, who was then a research associate of the Cutaneous Oncology and Therapeutics Research at the Miller School of Medicine, worked under the supervision of Sung "Bob" Hsia, a Chinese investigator who had studied with Nobel Prize laureate Edward Doisy, co-discoverer of vitamin K and oestrogen.

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"Hsia was around 80 at the time," Narain recalls. "He would say, 'I don't grasp these new genetic technologies, but never forget that biochemistry is the foundation of the body. That's what's at the end point of either the continuum of health or the onset of disease.'" He didn't forget. Narain argued with scientists who were convinced that genomics was the answer to all medicine's problems. To Narain, genomics was part of a

bigger equation that involved the study of proteins, products of metabolism and cellular lipids.


When Narain told the results of his experiment to Hsia, who had been working with CoQ10 for decades, his supervisor retorted: "There's no way that something that has lipids, enzymes and mitochondria machinery is going to kill a cancer cell, especially a melanoma. You screwed the experiment up."

A Berg researcher examines a patient sample Benedict Evans

Narain repeated the experiment. Other research groups replicated the experiment. It wasn't a fluke. "We didn't deliver genes, so it made me wonder what was going on. It had to go well beyond genomics. That wasn't really the cool thing to say at the time. It's still not the cool thing to say, but you have to follow the data."

He came up with a hypothesis, tested it, gathered the data and analysed it. It made no sense. He did come to one conclusion, though: hypothesis-driven science was not best suited to tackle complex diseases, especially cancer.

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In March 2005, Mitch Gray, the CEO of a private-equity firm based in Nashville, Tennessee, visited the university of Miami's department of dermatology where Narain worked. Gray had bought the rights to use the brand name Sea & Ski, a suntan lotion that had been popular in the 80s, and was looking for new dermatology products. Narain had a bad cold that day and he was about to go home when his chairman asked him to join a meeting with Gray and give a quick presentation about his work. "I wasn't feeling well and really didn't want to be there, so I was just flipping through my slides," Narain says. "when I briefly mentioned the CoQ10 work, Gray asked me to stop and explain further. I said that since he was there about skincare products, this was of no interest to him. Gray replied, 'Allow me to decide what I'm interested in.' He stopped me in my tracks."

When Narain finished his presentation, Gray called him aside and asked him to meet his Nashville team and his partner, Carl Berg. Berg was a former vending-machine repairman who had invested in Silicon Valley commercial property in the 60s. He was now a billionaire and a co-founder of Cupertino-based Mission West Properties, which controlled more than 700,000m<sup>2</sup> of Silicon Valley real estate. He was also an early investor in more than 100 tech companies, including Sun MicroSystems and NetLogic.

In 2006, Gray and Berg licensed the product containing CoQ10, which Narain had been researching, and the three founded a new company, Cytotech Labs, with Narain as scientific adviser. Narain, who was still based in Miami, continued to work on the product. Six months later, he called Berg with some news. He had tested the product on a number of different cancer cells. It had killed them. "He told me, 'I think there's a chance that there's something in your product that could have an effect on cancer,'" Berg recalls. "I was very concerned because I'd always been told that every cancer cell was different.

Gee, we're really stretching it now if this works on a number of cancers. I said, 'Call

me when you cure somebody.'"

Chilled to -80°C, a Berg freezer contains trial samples from more than 60,000 cancer, diabetes and neurological-disease patients Benedict Evans

A year after patenting the drug, Narain was contacted by an expert in intellectual property. The man, whose name Narain won't mention for privacy reasons, explained to him that his eight-year son was dying of Ewing's sarcoma, a rare and apparently incurable cancer of the lymph nodes. They had tried lots of therapies, both conventional and experimental. All had failed and now his son had only a few months to live. He wanted to try Cytotech's new cream. Narain explained that the cream wasn't being tested for sarcomas. "He told me, 'I know all that, but the approach that you're taking is different. I want to try it,'" Narain recalls. "I didn't want to create false hopes, but he was a pretty intense father who wouldn't take no for an answer." When they met, Narain acceded, while making clear to the boy's father and doctors that he and his company didn't think this approach had a rational basis for treating his son's cancer. "I did that because I couldn't tell you how it was to look in that father's eyes," Narain says. "It was desperation and just horrible to see."

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To proceed, Cytotech first had to obtain approval from the US Food and Drug Administration (FDA). When Cytotech's regulatory team submitted the paperwork to the FDA, they got approved in less than three hours.

For the treatment, the doctors applied the cream under the child's arms, behind the knees and behind the neck, where the lymph nodes are located. "Lymph nodes can absorb fats into the body," says Narain. "If you want the cream to drive into the skin, I guess if you get enough of it into lymph nodes then maybe some of it will get into the system and circulation. That was the rationale, but let me be very clear: there is no way that you would ever treat solid tumours like this. The likelihood

of this working was nil."

Eight months later, the child had no sign of cancer. "He's alive today and doing great," Narain says. "We had no idea what the hell would happen. That occurrence really gave us an insight that this was probably a really special molecule. When I heard the news,

I cried. No scientist expects that."

By late 2008, Narain had relocated to Cambridge, Massachusetts, and the company was renamed Berg Pharma. Narain felt frustrated with what he saw in clinics. "The way patients were treated often had nothing to do with their biology and their disease," he says. "I knew I had to start afresh and put biology at the forefront." Narain then pitched Berg the idea of developing a data-driven approach to finding drugs, using high-throughput molecular screening and artificial intelligence. Berg expressed interest. He was tired of the real-estate business and had decided to invest in companies with the potential to change the world. Narain's idea convinced him.

"For more than 50 years, I had avoided biotech because I felt the FDA was just one additional risk that I didn't want to take," Berg says. "But I believed this was so revolutionary that I was willing to take that kind of risk."

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By early 2010, the team had completed the first iteration of its cancer model: a map that depicted with unprecedented detail the cascade of biological events that lead from good health to cancer. "The machine's output is like an airline map, consisting of big hubs for most of the traffic, the New Yorks and the Londons, and lines going in and out of them," Narain says. "The hubs in the map represent the molecules that are either abundant or deficient in cancerous tissue relative to healthy tissue. The molecules at the hub become our drug. This is what the AI is telling us is the difference between health and disease. The platform flags the molecules that are abundant or in deficit in diseased cells, so we either feed these proteins or these enzymes back to the system, or we decrease or inhibit them to bring the system back to normal."

The cancer map had five hubs. The biggest hub was made by a group of enzymes that live inside the mitochondria. One of those enzymes was CoQ10. "When I saw that, it was a huge 'a-ha' moment for me," Narain says. "It was a validating moment. Remember, all these years I'm harbouring the thought that it can't be genomics, and now the AI was telling me that at the fulcrum of cancer is the mitochondria. Of course, in my mind, from all my previous experiments, this made total sense."

When Narain took the CoQ10 and fed it back to the in-vitro cancerous tissues, most cancer cells started to die off. Using Berg's intensive molecular data-tracking, Narain was finally able tounderstand why. The mitochondria, where CoQ10 is active and helps produce energy within the cell, not only supplies energy to the cell but also controls its ability to die. "Cancer cells are able to turn off the mitochondria and generate energy from lactate instead of oxygen," Narain says. "Because of that, cancer cells also lose the ability to die." Feeding back CoQ10 into the mitochondria reversed this effect, turning cancer cells into normal cells. "We re-taught

them how to undergo cell death."

One cloudy afternoon in December 2015, Niven R Narain gives WIRED a tour through Berg Pharma's white-walled laboratories in Framingham, 30km west of Boston. The place is more like a large biomedical research department than an eight-year-old pharmaceutical company, with more than 200 staff - including physicians, physicists and computer scientists - working in large rooms containing mass spectrometers and large servers. "What you see here is the most stringent, high-throughput, high-volume laboratory in the country," Narain explains. "We process more samples here than any academic or industry laboratory."

Berg also researches drugs for Parkinson's disease. This fridge is full of patients' samples Benedict Evans

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Narain is Guyanese born and was raised in the Bahamas, but his soft, calm voice belies no Caribbean influences. He is wearing a dark button-down shirt and a pinstripe suit. His dark hair is combed with a neat side parting, his face adorned with a goatee. As he ambles down the long corridors he stops to chat with his workmates, his manner jovial and affectionate.

Berg Pharma is currently studying more than 200 drugs, with many in pre-clinical studies, mostly targeting cancer, diabetes and neurological diseases. In the next few years, Narain expects the company to have at least one drug approved for various types of cancer and a new prostate cancer diagnostic method commercialised. Berg has ongoing drug research programmes for neurological diseases such as Alzheimer's and Parkinson's. "I think neurology is really the next cancer," says Narain. "Drug companies have shut down their neuro programmes because most trials have failed. We have no clue about the biology of those diseases."

Narain walks into a room full of freezers which store cell samples from more than 60,000 medical-school patients. Inside, the samples are stored in Eppendorf tubes. They are all annotated: Parkinson's; Alzheimer's; diabetes; cancer; lupus; inflammation. "We have cell samples and we also have the secretions that come out of the cells," Narain says. "There's a lot of information we can extract.

The genome is the template of the human body, but genes produce RNA, which in turn produces proteins and metabolites and lipids. That's our starting material."

Berg is planning to launch a diagnostic test for prostate cancer in 2017 in collaboration with the US Department of Defense, which made available hundreds of thousands of tissue samples from its employees. "Prostate cancer is one of the biggest issues in the military and they wanted us to come up with a better diagnostic test than the one currently available, the prostate-specific antigen [PSA], which is not very good," Narain says. "We discovered four biomarkers that are not only more predictive than PSA, but can separate the more aggressive forms so we can see if patients might need surgery. There were no markers for that." There is also a collaboration with Harvard Medical School on Project Survival to discover the first biomarker for pancreatic cancer, which usually goes undetected until the disease is very advanced. Of course, there's nothing in Berg's approach - which Narain calls "Interrogative Biology" - that's exclusive to cancer. It has been studying tissues from patients with Parkinson's since 2013, and Alzheimer's since 2014.

Berg is undertaking its BPM 31510 clinical trial with the same data-driven approach. It is collecting urine, serum and plasma from patients at each cycle of drug infusion, which takes place regularly over a 60-day period. These samples are then analysed in turn by 12 robotic mass spectrometers: five for proteomics, five for metabolism and two for lipidomics. (The genes are sequenced at the Mount Sinai Hospital in New York.) "I can tell you what you had for dinner ten days ago because it's still in your lipids," says Michael Kiebish, vice president of Systems Medicine at Berg. "You pick it up and you're like, 'Well, what is this?' We're picking up things that haven't been detected before. It was really unexplored territory. We're going to find things that no one has ever connected to a disease because we're measuring it for the first time. There is a wide open area for health data because, right

now, most people are focused on genetics. We're going beyond that."

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A Berg scientist feeds cancer cells to ensure they keep growing Benedict Evans

Leonardo Rodrigues, associate director of advanced analytics at Berg, agrees. "Genomics is important, but it gives us a static picture of what happens to us," he says. "It is like trying to know whether a restaurant is good only by looking at the recipes they are using. A lot of things happen beyond genomics. We can capture those cause-and-effect events to get a dynamic picture of what's going on. That leads to better drugs and biomarkers." Every time the team collect samples from patients, they measure tumours with CAT and PET scans. They also measure the concentration of the drug in the patients' plasma and keep track of how they are eating and sleeping. "Likely we were the first trial ever approved by the FDA to do this," says Narain.

The current trial has more than 100 participants from Cornell Weill Medical Center in New York, the University of Texas MD Anderson Cancer Center and the Palo Alto Medical Foundation. Although it's still in its initial phase, the early results are encouraging, indicating that the drug is effective in treating highly metabolic solid tumours in very sick patients with minimal side effects. "We're seeing the decrease of tumour sizes and we're seeing patients feeling energetic and doing much better," says Narain. "And we're even seeing tumours disappear in first phase of the trial, which is

rare for this type of patient."


There's one particular case that Narain remembers well. The patient was a male medic with bladder cancer. His doctor was one of Cornell University's leading gastro-intestinal experts but the patient had resisted all therapies. "I wrote in my notebook: 'First evidence of no sign of tumour activity in patient at the phase 1B trial,' says Narain. "The solid tumour was completely gone. Stunning. It validated everything for us. That day, I felt proud."

João Medeiros is WIRED's science editor. He curates the magazine's R&D section

Updated 25/04/16, 16:25: This article originally described Niven R Narain as an oncologist at Miami's Miller School of Medicine. He was a cancer researcher.