January 2012 Issue
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He Did It

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Fourteen hours after entering the world, Noah Rothberg stops breathing. His skin turns blue, his blood unable to feed his cells and tissues with enough oxygen. In a terrifying instant, the hospital room swarms with medical personnel. The newborn is rushed from the protective cradle of his mother’s arms to the neonatal intensive care unit. The NICU is dimly lit, with the drone of beeping monitors and wheezing respirators punctuated by the occasional infant’s cry or alarm. Specialists stabilize Noah, placing him in an incubator to warm his tiny body. He is placed under oxygen. An IV delivers fluids and drugs. Chest wires track his vital signs.

In the nearby waiting room, Noah’s father, Jonathan Rothberg, paces in shock. It has been a matter of only hours, but already it seems like a lifetime has passed since he and his wife, Bonnie, were celebrating their son’s birth. Now they are confronting an all-too-familiar nightmare. Three years before, the couple’s daughter, Jordana, was diagnosed at six months old with tuberous sclerosis complex, a rare genetic disorder that can cause benign tumors to form in the eyes, heart, kidney, skin, lungs, and brain. Symptoms range from mild to severe, but doctors warned that Jordana might never speak and could suffer from seizures and other life-threatening complications.

Still reeling from these possibilities, Rothberg tries not to fall apart in the face of Noah’s crisis. He spends a sleepless night on the waiting room couch as doctors run tests to figure out what’s wrong. What he finds most unbearable is the lack of answers. “Why can’t I have complete information on Noah?” he wonders.

To Rothberg, a biotech entrepreneur, “complete information” means viewing Noah’s genetic code to see whether he has an inherited disease. The twisted ladders of DNA that form each person’s genome are comprised of three billion “letters,” or chemical bases. Rothberg wants to read the “words,” or genes, spelled out by Noah’s unique sequence of these bases, which could reveal why his son is fighting to breathe. He thinks, “Why can’t we sequence his genome so we know what to worry about and what not to worry about?” But he understands that’s out of the question.

In 1980, British biochemist Frederick Sanger shared a Nobel Prize for developing a process to read the exact order of chemical bases in DNA. Scientists working on the Human Genome Project throughout the 1990s built factories of huge sequencing machines that used this method to collectively decode one human genome for the first time. It took longer than a decade and almost $3 billion to reach that milestone. As of July 1999, when Noah Rothberg is born, there’s still no faster, cheaper way to crack the genetic code.

Rothberg learned how to sequence DNA while working in a lab his junior year at Carnegie Mellon, where he studied to be a chemical engineer like his father. He is the sixth of seven children raised in a family of technology-minded entrepreneurs in New Haven, Conn. He often went on sales calls as a boy with his dad, Henry Rothberg, who founded Laticrete International, which makes adhesives for stone and ceramic tile.

During his senior year at Carnegie Mellon, Rothberg heard Steve Jobs speak in Hunt Library after the launch of the Macintosh; he had been clipping articles for years about the Apple co-founder and still has a 1982 Time magazine cover about the late computing legend. Jobs told the audience the secret to his success was to “just do it,” several years before Nike coined the phrase.

“I wanted to understand if Steve Jobs was made out of something different than the rest of us, but he explicitly said you are really defined by what you do,” Rothberg recalls. “It was that ‘aha’ moment, where I realized life was about doing as opposed to hesitating. And it reminded me of something my mother told me: You don’t go through life with your IQ on your forehead—what matters is what you do with yourself.”

After graduating from Carnegie Mellon in 1985, Rothberg saw his chance to “just do it” by applying his chemical engineering degree, and what he had learned about DNA, to the burgeoning field of molecular biology: “I realized there were huge opportunities for an engineer to systematically improve biological methods like DNA sequencing.”

In 1991, after earning his PhD in biology from Yale, he started a company called CuraGen in his basement. On his team were Craig L. Wiener (S’85), Gregory T. Went (E’85), Leonard D. Bogarad, and John W. Simpson. There, he mined the troves of genetic data being generated by the Human Genome Project for new drug targets. For instance, the company developed an antibody now in clinical trials for treatment of breast cancer and melanoma. It was the height of the dot-com boom, and stocks of genomics companies, in particular, soared. CuraGen filed its public offering in 1998 and soon afterward became the fastest rising stock on NASDAQ. At its peak, CuraGen had a $5 billion market cap—higher than American Airlines.

In 2001, CuraGen landed a $1.5 billion deal with Bayer to develop drugs for obesity and diabetes. Rothberg was ranked 37th that year on the Fortune magazine list of America’s 40 richest under 40, with an estimated net worth of $168 million. “I would be on the top of your rich list if I had skipped graduate school,” he quipped to the publication with trademark exuberance.

Molecular biologist Kevin Davies, editor of the genetics journal Nature Genetics, follows Rothberg’s career in his 2010 book, The $1,000 Genome, about the evolution of DNA sequencing technology. Rothberg reminds him of the boy trapped in a man’s body, played by Tom Hanks, in the movie Big. “He’s got this larger-than-life, eccentric, almost-childlike personality,” Davies says. “By childlike, I mean enthusiastic, loud, excitable, and passionate—you don’t see any of the cynicism or negativity that you may encounter in other industry executives. To Jonathan, nothing is impossible.”

Perhaps that’s why, in the frightful days following Noah’s birth, Rothberg pulls a yellow notepad out of his briefcase and begins drawing. He is inspired by his latest copy of the computer magazine InfoWorld, whose cover touts Intel’s Pentium microprocessor. It gives him an idea for a new approach to DNA sequencing—on a chip: “Those Henry Ford-like processes where they set up hundreds of machines and required hundreds of people to decode the first genome wouldn’t work for my son—they were too slow and expensive. Instead of having a factory with hundreds of square feet, you could do everything within a few centimeters. It would be highly parallel, efficient, and low cost.”

Fast, affordable genome sequencing could transform industries as diverse as biomedicine, agriculture, nanotechnology, and energy. For instance, doctors could use the technology to treat cancer patients with custom drugs designed to attack genetic weaknesses in their tumors. DNA sequences could function as identifying tags to track the global spread of infectious bacteria and viruses. Discovery of new genes could help farmers breed pest-resistant, high-yield supercrops. Engineers could develop newer, stronger biomaterials or designer microbes for renewable fuels.

“DNA sequencing is going to affect everything,” says Rothberg, predicting it will become a $100 billion industry. “This is biology’s century, just as physics was the foundation of the last century.”

In the hospital, waiting for news about Noah, Rothberg was unknowingly about to start that revolution. “Everybody does something different in those situations,” he says. “For me, sketching and doing calculations were a way to take my mind off the fact my son wasn’t breathing, so I wouldn’t have a breakdown.”

His conceptual idea leads to a breakthrough. He envisions cutting out a long, costly step of the Sanger method requiring bacteria to help sequence DNA fragments. He develops, instead, a way to attach those fragments to a slide or bead, making it possible to carry out hundreds of thousands of sequencing reactions at the same time in miniature.

Noah, after a few days in the NICU, makes a dramatic recovery. Doctors suspect he suffered a reaction to a medication administered during labor. The family goes home, and Rothberg is on paternity leave for two weeks. He infuriates his wife by spending the time immersed in equations rather than diapers.

Eventually, his ideas for a DNA sequencing machine evolve into the company 454 Life Sciences, which is launched as a CuraGen subsidiary. But the news isn’t all good. In 2000, the biotech market crashes, along with all of the other dot-coms. CuraGen enters stock freefall and is acquired by Celldex Therapeutics for just $93.5 million in stock. Nevertheless, Rothberg is maintaining his focus on 454, determined to see his sequencer through to commercial launch.

That happens in August 2005, when Rothberg and his colleagues publish proof-of-concept of their technology in the scientific journal, Nature, announcing their method could decode a bacterial genome some 100 times faster than the Sanger technique—an unprecedented triumph. “It was a major advance because it achieved the important goal of better, faster, and cheaper sequencing of whole genomes,” explains Richard Lifton, chair of the department of genetics at Yale and Rothberg’s longtime collaborator. “This was really the first entrant in the market of next-generation sequencing, and it has spurred a huge amount of research and development, creating a vibrant field that is rapidly evolving.”

454 and colleagues pull off several headline-grabbing scientific feats, such as sequencing the Neanderthal and woolley mammoth genomes and identifying a mysterious virus triggering the collapse of honeybee colonies. The biggest achievement comes on May 31, 2007, when Rothberg presents James Watson—co-discoverer of the molecular structure of DNA—with a portable hard drive containing 24 billion characters of the Nobel laureate’s personal genome; the analysis with the 454 sequencer took just 13 weeks and $1 million to complete. It’s a giant leap forward from the decade of time and billions of dollars it took to finish the Human Genome Project.

At a press conference that morning, Rothberg announces, “This is the end of one quest—the dream to sequence a genome—and the beginning of another quest” to routinely sequence a person’s genome for $1,000 or less. Reaching this milestone could put DNA sequencing technology within reach of anybody who would want it.

Science magazine recognizes these sequencing innovations as one of the top 10 breakthroughs of the year. But Noah Rothberg—at this point a healthy and precocious 8-year-old—isn’t impressed. When his father proudly informs his son that he’d just handed Jim Watson his DNA sequence, Noah asks what that means.

“That I scanned his genome,” Rothberg explains.

“Why don’t you build something that will scan people’s minds so you know what they are thinking?” Noah replies.

Instead of dismissing his son’s flight of fancy, Rothberg thinks about it from a researcher’s perspective—a device that could translate chemical signals in the brain into digital information. Most sequencers—including the 454 machine—decode DNA by coupling light-producing molecules to the chemical bases, taking pictures, and then analyzing the resulting images. Rothberg, inspired once again by his son, imagines replacing this optical technology with a silicon microchip, like you might find in your MP3 player or smartphone. The chip would hold millions of sensors that directly read the electrical signals produced during chemical reactions that occur during DNA sequencing—much like Noah’s mind reader.

The result is the Personal Genome Machine manufactured by Rothberg’s latest business venture, called Ion Torrent. Sequencers typically cost hundreds of thousands of dollars and are the size of a small refrigerator, but the Personal Genome Machine sells for just under $50,000 and is no bigger than a desktop printer. Initially the instrument reads only 10 to 20 million bases per run, compared with billions for some of its competitors. But sequencing a sample with a high degree of accuracy only takes an hour or two—compared with days on the bigger machines.

Already, Ion Torrent made international news this past summer when its device rapidly identified the virulent strain of E. coli responsible for killing more than 50 people across Europe. It’s also being put to the test at Massachusetts General Hospital to analyze cancer-linked genes in tumor cells and at the Woods Hole Marine Biological Laboratory to track down sources of fecal contamination in drinking water. And its key advantage, according to Rothberg, is scalability.

In 1965, Intel co-founder Gordon Moore described a trend stating that the number of transistors that can be placed inexpensively on an integrated circuit doubles every two years. Moore’s law has held true for decades, and if the Personal Genome Machine follows this maxim, then it will be easy and cheap to scale up the chips to contain 10 to 100 times as many sensors—in much the way the semiconductor transformed the computing industry, says Ion Torrent President and COO Gregg Fergus.

This year, the company expects to have a machine that can decode in two hours all 20,000 human genes that code for proteins—and in a few more years, the $1,000 genome could be within reach. “It’s exactly analogous to when mainframe computers were replaced by minicomputers and then personal computers and now our phones are more powerful than our first computers,” says Fergus.

Rothberg imagines a future when a personal genome machine will be found in every doctor’s office, where patients will have their genomes sequenced as routinely as they get x-rays. It may sound like science fiction, but industry expert Davies says the vision is not farfetched. “There is going to be a great market for a machine that can miniaturize and simplify DNA sequencing so almost any researcher or clinician has access to it,” he says. “I think Jonathan has as good a shot as anyone of making that happen.”

The media agrees. Forbes magazine showcased Rothberg and his “gene machine” on a recent cover. In addition, the university trustee is the first person to be recognized twice by The Wall Street Journal’s Technology Innovation Awards, which named him as a 2011 runner-up for his work with Ion Torrent; 454 earned him a gold award in 2005. And, he is also the first person to be named as The World Economic Forum’s Technology Pioneer three separate times for the companies he founded.

Life Technologies is certainly betting on Rothberg; the global biotech corporation acquired Ion Torrent two years ago in a blockbuster deal for $725 million, with Rothberg staying on as CEO. Today, just as he accompanied his father on the road, his own five children sometimes join him on business trips, including Jordana, who is a healthy, Facebook-loving teenager.

It was on one of those trips that Noah—who struggled so mightily for his first breaths—showed his “old man” that at the age of 11 he had learned a thing or two about success. Rothberg had taken him along when he met with Moore, Intel’s chairman emeritus, presenting him with his personal genome sequenced by the Ion Torrent machine. Moore was impressed. “Afterwards,” says Rothberg, “Noah told me the next time I start a company, he gets 50 percent.”?

Jennifer Bails is an award-winning freelance writer. She is a regular contributor to this magazine.



Related Links:
Trustee Opens Innovators Forum
$1,000 Genome in Two Hours by 2012, Says CEO of Ion Torrent

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