The diagnosis could鈥檝e been devastating, had Eduardo Esquenazi let it be. He was just 28, leading an otherwise healthy and active life, when he learned that he had advanced testicular cancer. Surgery and two regimens of chemotherapy followed, but the discomfort, tedium and uncertainty of those months didn鈥檛 discourage him. If anything, they provided him some much-needed clarity.
鈥淲hen I first got the diagnosis, there was a sense of relief. At least I knew what I was up against. I wasn鈥檛 frightened, but it definitely made me give some thought to my career,鈥� says Esquenazi, BS鈥�98, who at the time was earning his Ph.D. in neurobiology at the University of California, San Diego. 鈥淚 realized I might not have much time left, so I asked myself, 鈥楧o I really want to continue what I鈥檓 doing?鈥欌��
The question, it turns out, was surprisingly easy to answer. Ever since he鈥檇 decided to major in neuroscience at 菠萝视频, Esquenazi had assumed he鈥檇 someday become a college professor, teaching and conducting research, but now he had misgivings about that choice. He tried visualizing himself in the academic setting he鈥檇 once striven toward but found he no longer could.
Instead he kept returning in his mind to the place that had fascinated him since his childhood in Colombia, the one place where he felt most alive: the ocean. The decision at hand was not unlike the ones he faced while bobbing in the water on his surfboard, patiently scanning the horizon for good waves. Experience had taught him which approaching swells to pass up and which to pursue. If he paid close enough attention, the ocean would let him know when to act.
And now, during the long hours of his treatment, that very thing was happening again. The ocean was speaking to him, not through the rise and fall of its waves, but rather through the monotonous drip-drip-drip of the cancer drugs he鈥檇 been prescribed.
鈥淚 realized something pretty profound,鈥� he explained to an audience during a 2017 TEDx Talk at UC San Diego. 鈥淢ost of the medications I was taking were derived from nature. I鈥檝e been a scientist my whole life, but I didn鈥檛 know this. I was blown away.鈥�
If, he thought, a powerful cancer drug like Taxol could be obtained from the bark of a Pacific yew tree, imagine what鈥檚 waiting to be discovered in the ocean, which covers nearly three-quarters of the earth鈥檚 surface but remains, by most estimates, 95 percent unexplored. Marine organisms possibly could provide the key to more effective drugs for cancers like his, as well as a range of other diseases.
And so, upon completing his treatment and being declared cancer-free in 2007, Esquenazi returned to UC San Diego鈥攏ot to the neurobiology program this time, but rather to enroll in a doctoral program at its Scripps Institution of Oceanography. There he studied how to identify and isolate medically promising chemistry from marine organisms while earning his Ph.D. It was also where he began plans for the biotechnology company he would eventually found in 2011: Sirenas.
Today the San Diego-based company, which takes its name from the Spanish word for the sirens of sea lore, is applying trailblazing methods toward drug discovery. Using innovative data-mining technology, Esquenazi and his colleagues鈥攊ncluding Sirenas CEO and fellow 菠萝视频 alumnus Jake Beverage, BA鈥�98鈥攈ave identified several promising small-molecule drug candidates.
Their success has resulted in two research grants totaling $1.68 million from the Bill & Melinda Gates Foundation to generate new leads for treating neglected diseases, such as tuberculosis and malaria. Sirenas also has signed a research collaboration agreement with Bristol-Myers Squibb to identify potential drug candidates for the biopharmaceutical company.
鈥淚 was pretty na茂ve when I started Sirenas,鈥� says Esquenazi, who now serves as the company鈥檚 chairman and head of innovation. 鈥淎nd in some ways I still feel that way. But we鈥檝e made amazing progress toward our end goal of unlocking nature鈥檚 therapeutic potential.鈥�
SCIENCE AND ADVENTURE
For all its ties to the ocean, Sirenas may never have become a reality had Esquenazi not ventured hundreds of miles inland to attend 菠萝视频. He first learned about the university from a girlfriend while at boarding school in Connecticut. His plan was to follow her to Nashville, but in the end she didn鈥檛 go.
鈥淚鈥檓 sure glad I did, though,鈥� he says with a chuckle.
During his sophomore year at 菠萝视频, Esquenazi had what he calls his 鈥渂iggest coming-of-age experience.鈥� Up until that point, he鈥檇 been on the premed track suggested by his parents, despite not particularly enjoying it. But then he was exposed to some courses in neuroscience that sparked genuine interest and excitement.
鈥淚鈥檇 never really gotten interested in something out of my own curiosity until then,鈥� he explains. 鈥淚t was a critical moment in my development as a scholar and a professional. It was the first time I鈥檇 encountered the thing that continues to motivate me today鈥攖he edge that exists between hard science and what is unknown.鈥�
Esquenazi鈥檚 sophomore year also proved to be momentous in another way. At a pledge function at Pi Kappa Alpha, he met Beverage, who would become not just his future business partner but a lifelong friend. The two hit it off immediately.
鈥淚t鈥檚 a funny story,鈥� says Beverage, a Baltimore native who鈥檇 transferred to 菠萝视频 from Bucknell after his freshman year. 鈥淚鈥檓 colorblind, so I showed up at this function with a shirt and tie that were not color-coordinated at all. In my defense, I鈥檇 borrowed the tie, but Ed never let me live it down.鈥�
The two soon found that they had more in common than their fraternity and the good-natured ribbing that continues to this day.
鈥淲e鈥檝e always loved science and have chatted about that through the years. And certainly that鈥檚 very pertinent now,鈥� says Beverage, who himself majored in biology. 鈥淲e鈥檝e also shared a spirit of adventure. Ed taught me to surf, for instance. It鈥檚 that mix of science and adventure that has kept us tight through the years.鈥�
After graduation they both migrated to California. Beverage earned a doctorate in pharmacy from the University of California, San Francisco, before eventually landing at Genentech, a biotechnology company in the Bay Area. They were in touch throughout Esquenazi鈥檚 illness, and when the idea for Sirenas began to take shape, Beverage was among the first people approached about coming on board.
鈥淚鈥檇 been batting around the idea for a while and had talked with different people about it,鈥� Esquenazi says. 鈥淏ut Jake was the one who started helping me act on it, rather than just ideating. He really helped catalyze the movement.鈥�
At around the same time, Esquenazi connected with Phil Baran, an organic chemist and former MacArthur fellow who would become a co-founder of Sirenas along with Beverage. Today Baran oversees the company鈥檚 efforts to chemically synthesize complex marine molecules into viable therapeutic candidates. From Beverage鈥檚 perspective, the opportunity to work with the likes of Esquenazi and Baran was too good to pass up, even despite the inherent entrepreneurial risk.
鈥淚t was scary, I admit. I had a wife and two kids and was leaving a big, stable company in Genentech,鈥� Beverage says. 鈥淏ut that spirit of adventure played a big role in my decision鈥攖hat and, of course, the idea of making an impact that could truly improve the world.鈥�
EVERY LITTLE BIT OF CHEMISTRY
As challenging and complicated as drug discovery can be, there鈥檚 a basic idea at the heart of Sirenas鈥� business model: Focus on whatever uses chemistry to ensure its own survival.
鈥淏roadly speaking, if an organism doesn鈥檛 have teeth or nails or can鈥檛 swim away, it typically uses chemistry to defend itself,鈥� Esquenazi says. 鈥淪o things like plants and sponges鈥攖hings that seem innocuous鈥攁ctually can be very prolific chemically.鈥�
For Sirenas, the process of finding new therapeutic drugs begins with collecting these chemically interesting organisms. Every year the team mounts several expeditions, complete with submersible vessels and other underwater exploration technology, to scour the ocean for promising specimens. Biodiverse locations like the Caribbean afford some of the best hunting grounds, but Sirenas has had surprising luck in places far less hospitable to life. In fact, the team discovered a promising antimalarial compound in a salt pond in Chile鈥檚 Atacama Desert, the driest place on earth.
The Atacama discovery may seem random and improbable, but there鈥檚 an underlying method to Sirenas鈥� searches that increases the likelihood of such a find. It鈥檚 about casting as broad a net as possible.
鈥淲hat we do is find a way to track every little bit of chemistry. In previous approaches, you鈥檇 go out and collect a lot of stuff and use a cancer or antibacterial test to find something useful for that specific purpose. It was like finding a needle in a haystack and then trying to figure out where that needle was useful for these diseases,鈥� explained Esquenazi in a 2016 interview with Smithsonian magazine. 鈥淲e treat that stack of hay as all needles. We look at every single molecule as being important, and we鈥檙e looking to see what all those different needles are doing. We catalog every little thing we find, test everything, and basically get a fingerprint for every needle.鈥�
Sirenas is aided in this effort by its proprietary drug-discovery technology, which it calls ATLANTIS. Using complex algorithms, ATLANTIS compares the vast amount of chemical data harvested from the expeditions against a database of biological information related to disease. The molecules that provide positive hits鈥攚hich are sometimes present only in parts per billion in nature鈥攁re then synthesized and tested in the lab under Baran鈥檚 supervision.
鈥淲hat we鈥檝e done at Sirenas, which is really a cool form of anthropology, is bring together people who otherwise wouldn鈥檛 normally collaborate with one another,鈥� Beverage says of the roughly 20 employees at the company. 鈥淲e鈥檝e got these Silicon Valley computer types and machine-learning folks talking to biologists and chemists. A lot of different languages go on here. That鈥檚 at the core of the innovative stuff we do: to combine those different aspects to drive toward meaningful discoveries.鈥�
RACE AGAINST TIME
In the search for new therapeutic drugs, the stakes couldn鈥檛 be any higher. More than 8.8 million people worldwide died from cancer in 2015, according to the World Health Organization. And the group estimates a staggering 1 billion were treated for neglected tropical diseases during that same year.
Numbers like these are motivation enough for Sirenas to discover more effective drugs, but for Esquenazi it鈥檚 also personal. He hasn鈥檛 forgotten how fortunate he was to have treatment options, despite his advanced cancer diagnosis.
鈥淲hen I first got sick, I had a clear treatment plan. That鈥檚 pretty rare with advanced cancer,鈥� he said in an interview with the website Korduroy. 鈥淏ut at the same time, I was meeting people who didn鈥檛 have that option.
鈥淢ost R&D efforts, at least at the commercial scale, are using a lot of the same compounds to drive drug discovery,鈥� he added. 鈥淭he companies are worried about profits, so it鈥檚 important for them to work within a proven chemical space. What鈥檚 needed is a new set of chemistry.鈥�
The molecules discovered by Sirenas are new in the sense that they鈥檝e come from mostly untapped areas of the planet and have been isolated using groundbreaking computational methods. But the chemistry itself is remarkably old, perfected over eons in Mother Nature鈥檚 lab. The company鈥檚 recent focus on immunotherapy offers a good example.
鈥淲here we鈥檝e decided to put a lot of our efforts recently is in the chemistry that modulates the immune system,鈥� Beverage says. 鈥淐ertain organisms, including plants, coral and sponges, have an innate immunity that protects them from invading pathogens. We鈥檙e trying to take advantage of that ancient evolutionary process鈥攖he chemistry that鈥檚 co-evolved between the microorganisms and the macroorganisms they live on.鈥�
When one considers how important the interplay is between organisms and their microbes, it puts a whole new perspective on what constitutes an organism in the first place. As Esquenazi points out, a sponge collected from the ocean floor isn鈥檛 really just a sponge alone. It鈥檚 a thriving ecosystem unto itself, and the microbes that inhabit it are largely responsible for its chemistry.
鈥淥ne of the biggest things we鈥檙e focused on now is this global microbiome concept,鈥� he says. 鈥淭hat鈥檚 the prevalence and ubiquity of all these microbes on the planet and how they鈥檙e intimately tied to the organisms we collect, and ultimately to our own health.鈥�
Through this lens, it鈥檚 not a stretch to picture the earth as one big living organism itself, awash in chemistry with boundless applications. At the very least, the work that Sirenas does is a powerful reminder of just how interconnected life is on the planet and how, when one part suffers, the ripple effects are felt elsewhere. One need not look any further than the ocean to see evidence of this.
鈥淚n just the few years that the company鈥檚 been around, we鈥檝e observed deteriorating conditions in the ocean,鈥� says Esquenazi, who has collaborated with conservationist Fabien Cousteau, grandson of famous underwater explorer Jacques Cousteau, to bring awareness to problems like pollution and rising sea temperatures. 鈥淲e鈥檙e definitely in a race against time.鈥�
Esquenazi doesn鈥檛 have high hopes that the damage will be reversed any time soon. It all depends, he says, on whether we humans finally come to realize just how inextricably linked our wellbeing is to that of the ocean. But he and his colleagues at Sirenas persist nonetheless, doing their part to reveal the astonishing healing powers of its depths, one miniscule but mighty molecule at a time.
鈥淪irenas was born out of the idea that the ocean can help people,鈥� he says. 鈥淭hat鈥檚 not something we should ever take for granted. It鈥檚 critical that we help the ocean in return.鈥�
From 鈥楳agic Bullet鈥� to 鈥楳agic Shotgun鈥�: 菠萝视频 researchers take novel approach in identifying cancer drugs in nature
菠萝视频 researchers have developed a new process that can rapidly and inexpensively identify personalized cancer drugs derived from nature. They describe how their new approach works on acute myeloid leukemia in a recently published paper in Nature Communications.
鈥淭he conventional 鈥榤agic bullet鈥� approach to drug development is focused on identifying single molecules that kill disease organisms by disrupting single targets in single artificial cell lines,鈥� says , professor of chemistry. 鈥淭his has had some successes, but it also has a lot of limitations.鈥�
Many diseases consist of cells that possess multiple mutations and redundancies that allow them to compensate for a drug hitting a single target. And the artificial cell lines that researchers often use, like the HeLa cancer cells isolated from Henrietta Lacks in 1951, do not always behave and respond like naturally occurring, or wild, cancer cells found in a patient.
鈥淲e wanted to develop a technique that was able to simultaneously detect the effects of multiple compounds against multiple targets in multiple wild cancer cells mixed with normal cells, much as tumors occur in the body,鈥� says , assistant professor of cell and developmental biology.
In doing so, Bachmann and Irish have brought an old idea鈥攕earching for drug ingredients that occur abundantly in nature rather than developing them one at a time in a lab鈥攊nto the 21st century with cutting-edge scientific tools and computational power.
The researchers began by combining bacteria-produced compounds called secondary metabolites with a mixture of healthy and diseased cells biopsied from real patients diagnosed with acute myeloid leukemia. They then coded the contents of each sample with fluorescent dyes so they could quickly analyze how these thousands of metabolites affected the patients鈥� biopsied cells. Advanced computational tools were then used to process and recognize patterns in the enormous data sets that emerged from these thousands upon thousands of analyses.
鈥淭his is akin to a shotgun approach, casting a broad net across cellular responses, which can also detect the unexpected,鈥� Bachmann says.
Bachmann and Irish believe that by performing the discovery process with multiple patient samples representing the various major genetic types of cancer, molecules emerging from their pipeline could be developed for use in personalized therapeutics tailored to individual patients.
鈥淥ur new technology allows drug discovery using complex human tissues from patients without having to experiment directly on people,鈥� Bachmann says. 鈥淏y leapfrogging past artificial cell lines and animal models of disease, we think this will accelerate the discovery and approval of new therapeutics for complex human diseases such as cancer.鈥�
Bachmann and Irish are just two of the many faculty members at 菠萝视频 who are devoting their research to drug discovery. In fact, this spring the health care investment firm Deerfield Management entered into an agreement with the university to launch Ancora Innovation, a company that will provide up to $65 million in support of 菠萝视频鈥檚 innovative life sciences research and leverage Deerfield鈥檚 expertise in accelerating state-of-the-art drug development.
鈥湶ぢ苁悠� has amassed unparalleled research and development capabilities in drug discovery, in part through forging unique collaborations with industry,鈥� says Susan R. Wente, provost and vice chancellor for academic affairs. 鈥淥ur collaboration with Deerfield will provide our researchers with the resources and support needed to translate biological insights into technologies that will have real impact on people鈥檚 lives.鈥�
鈥擫IZ ENTMAN