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鈥檚 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鈥檚 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鈥檚 father, , 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鈥檚 birth. Now they are confronting an all-too-familiar nightmare. Three years before, the couple鈥檚 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鈥檚 crisis. He spends a sleepless night on the waiting room couch as doctors run tests to figure out what鈥檚 wrong. What he finds most unbearable is the lack of answers. 鈥淲hy can鈥檛 I have complete information on Noah?鈥� he wonders.
To Rothberg, a biotech entrepreneur, 鈥渃omplete information鈥� means viewing Noah鈥檚 genetic code to see whether he has an inherited disease. The twisted ladders of DNA that form each person鈥檚 genome are comprised of three billion 鈥渓etters,鈥� or chemical bases. Rothberg wants to read the 鈥渨ords,鈥� or genes, spelled out by Noah鈥檚 unique sequence of these bases, which could reveal why his son is fighting to breathe. He thinks, 鈥淲hy can鈥檛 we sequence his genome so we know what to worry about and what not to worry about?鈥� But he understands that鈥檚 out of the question.
In 1980, British biochemist 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鈥檚 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 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 , 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 magazine cover about the late computing legend. Jobs told the audience the secret to his success was to 鈥渏ust do it,鈥� several years before Nike coined the phrase.
鈥淚 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,鈥� Rothberg recalls. 鈥淚t was that 鈥榓ha鈥� moment, where I realized life was about doing as opposed to hesitating. And it reminded me of something my mother told me: You don鈥檛 go through life with your IQ on your forehead鈥攚hat matters is what you do with yourself.鈥�
After graduating from Carnegie Mellon in 1985, Rothberg saw his chance to 鈥渏ust do it鈥� by applying his chemical engineering degree, and what he had learned about DNA, to the burgeoning field of molecular biology: 鈥淚 realized there were huge opportunities for an engineer to systematically improve biological methods like DNA sequencing.鈥�
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鈥�85), Gregory T. Went (E鈥�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鈥攈igher 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 magazine list of America鈥檚 40 richest under 40, with an estimated net worth of $168 million. 鈥淚 would be on the top of your rich list if I had skipped graduate school,鈥� he quipped to the publication with trademark exuberance.
Molecular biologist Kevin Davies, editor of the genetics journal , follows Rothberg鈥檚 career in his 2010 book, , about the evolution of DNA sequencing technology. Rothberg reminds him of the boy trapped in a man鈥檚 body, played by Tom Hanks, in the movie Big. 鈥淗e鈥檚 got this larger-than-life, eccentric, almost-childlike personality,鈥� Davies says. 鈥淏y childlike, I mean enthusiastic, loud, excitable, and passionate鈥攜ou don鈥檛 see any of the cynicism or negativity that you may encounter in other industry executives. To Jonathan, nothing is impossible.鈥�
Perhaps that鈥檚 why, in the frightful days following Noah鈥檚 birth, Rothberg pulls a yellow notepad out of his briefcase and begins drawing. He is inspired by his latest copy of the computer magazine , whose cover touts Intel鈥檚 Pentium microprocessor. It gives him an idea for a new approach to DNA sequencing鈥攐n a chip: 鈥淭hose Henry Ford-like processes where they set up hundreds of machines and required hundreds of people to decode the first genome wouldn鈥檛 work for my son鈥攖hey 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.鈥�
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.
鈥淒NA sequencing is going to affect everything,鈥� says Rothberg, predicting it will become a $100 billion industry. 鈥淭his is biology鈥檚 century, just as physics was the foundation of the last century.鈥�
In the hospital, waiting for news about Noah, Rothberg was unknowingly about to start that revolution. 鈥淓verybody does something different in those situations,鈥� he says. 鈥淔or me, sketching and doing calculations were a way to take my mind off the fact my son wasn鈥檛 breathing, so I wouldn鈥檛 have a breakdown.鈥�
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鈥檛 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, , announcing their method could decode a bacterial genome some 100 times faster than the Sanger technique鈥攁n unprecedented triumph. 鈥淚t was a major advance because it achieved the important goal of better, faster, and cheaper sequencing of whole genomes,鈥� explains Richard Lifton, chair of the department of genetics at Yale and Rothberg鈥檚 longtime collaborator. 鈥淭his 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.鈥�
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鈥攃o-discoverer of the molecular structure of DNA鈥攚ith a portable hard drive containing 24 billion characters of the Nobel laureate鈥檚 personal genome; the analysis with the 454 sequencer took just 13 weeks and $1 million to complete. It鈥檚 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, 鈥淭his is the end of one quest鈥攖he dream to sequence a genome鈥攁nd the beginning of another quest鈥� to routinely sequence a person鈥檚 genome for $1,000 or less. Reaching this milestone could put DNA sequencing technology within reach of anybody who would want it.
magazine recognizes these sequencing innovations as one of the top 10 breakthroughs of the year. But Noah Rothberg鈥攁t this point a healthy and precocious 8-year-old鈥攊sn鈥檛 impressed. When his father proudly informs his son that he鈥檇 just handed Jim Watson his DNA sequence, Noah asks what that means.
鈥淭hat I scanned his genome,鈥� Rothberg explains.
鈥淲hy don鈥檛 you build something that will scan people鈥檚 minds so you know what they are thinking?鈥� Noah replies.
Instead of dismissing his son鈥檚 flight of fancy, Rothberg thinks about it from a researcher鈥檚 perspective鈥攁 device that could translate chemical signals in the brain into digital information. Most sequencers鈥攊ncluding the 454 machine鈥攄ecode 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鈥攎uch like Noah鈥檚 mind reader.
The result is the manufactured by Rothberg鈥檚 latest business venture, called . 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鈥攃ompared 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鈥檚 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鈥檚 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鈥攊n 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鈥攁nd in a few more years, the $1,000 genome could be within reach. 鈥淚t鈥檚 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,鈥� says Fergus.
Rothberg imagines a future when a personal genome machine will be found in every doctor鈥檚 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. 鈥淭here 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,鈥� he says. 鈥淚 think Jonathan has as good a shot as anyone of making that happen.鈥�
The media agrees. magazine showcased Rothberg and his 鈥済ene machine鈥� on a recent cover. In addition, the university trustee is the first person to be recognized twice by 鈥檚 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鈥檚 Technology Pioneer three separate times for the companies he founded.
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鈥攚ho struggled so mightily for his first breaths鈥攕howed his 鈥渙ld man鈥� 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鈥檚 chairman emeritus, presenting him with his personal genome sequenced by the Ion Torrent machine. Moore was impressed. 鈥淎fterwards,鈥� says Rothberg, 鈥淣oah told me the next time I start a company, he gets 50 percent.鈥�?
Jennifer Bails is an award-winning freelance writer. She is a regular contributor to this magazine.
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