Texas A&M Chemist Builds on Natural Systems to Fight Human Disease
Romo (maroon shirt), working in the LINCHPIN laboratory alongside (from left) Dr. Lee Jennings, assistant research scientist, and Dr. Jing Li, assistant director.
Texas A&M Chemist Builds on Natural Systems to Fight Human Disease
June 11, 2012
"Texas A&M has provided laboratory space as well as initial seed funding for LINCHPIN, which at its core is attempting to translate basic research findings to potential treatments for human disease. It's sort of a natural outgrowth of the things we were already doing. I thought there would be a lot of possibilities for collaborations, not only locally, but nationally and internationally as well. So far, 20 different projects are under way with more than 20 scientists worldwide."
Solutions sometimes can be found in unexpected places. Take, for instance, the bottom of the ocean.
For more than a decade, Texas A&M University chemist and former student Dr. Daniel Romo has been squeezing life-saving answers out of sea sponges found in the chilly waters off the coast of New Zealand in an effort to fight cancer and other human diseases -- work that he believes merely scratches the promise-laden surface found at the crossroads of chemistry and biology.
Romo, who earned bachelor's degrees in both subjects from Texas A&M in 1986, is a master of synthetic manipulation; a middleman with a unique set of skills capable of changing the high-stakes game of human disease -- from diagnosis and treatment to prevention and possible cures -- with the help of solutions provided by Mother Nature herself.
His pioneering research explores the untapped potential of natural products -- specifically, organisms found in nature, from sea sponges to plants to bacteria, which he synthesizes in his laboratory in hopes of exploiting their utility in basic studies of human cell biology and as lead compounds for drug development.
"Our most successful example is Pateamine A, a compound that comes from marine sponges and that the lab is currently working on to determine its usefulness as an anti-cancer agent," Romo says. "That is, it is able to kill cancer cells, and we want to find out how useful it is in doing that."
As novel as its name, LINCHPIN opened its doors in September 2010 in fulfillment of Romo's long-term vision of a universal haven for all things natural-products research. Beyond experience, it is equipped with a plethora of specialized instrumentation necessary to perform chemical synthesis, derivatization methods, isolation and purification of bioactive natural products and related small molecules. Most importantly, LINCHPIN houses personnel with expertise in chemical synthesis and derivatization of natural products on microscale as well as isolation of natural products.
"It made sense to me that I had all of these collaborators who were interested in bioactive small molecules, including natural products, and that we had the expertise to manipulate these natural products and synthesize them if warranted," Romo says. "We were in an ideal situation to help these collaborators better understand what these small molecules were doing inside cells. I thought it would be nice to have a lab separate from my research group that basically utilizes our methods to prepare cellular probes from natural products and in this way more easily interact with these various collaborators."
Romo serves as the inaugural director for LINCHPIN, which he describes as a collaborative headquarters for a melting pot of organic experts. Its acronym-inspired nickname is fitting, given that the center is a literal linchpin that bridges a gap between the chemists who isolate small organic molecules from natural resources and the biologists who will apply them to the transitional research that serves as the critical underpinning for cutting-edge medical studies.
"Texas A&M has provided laboratory space as well as initial seed funding for LINCHPIN, which at its core is attempting to translate basic research findings to potential treatments for human disease," Romo says. "It's sort of a natural outgrowth of the things we were already doing. I thought there would be a lot of possibilities for collaborations, not only locally, but nationally and internationally as well. So far, 20 different projects are under way with more than 20 scientists worldwide."
Romo's breakthrough work with PatA certainly has been one of his biggest worldwide attention-getters to date. In 1998 he and his longtime research partner Prof. Jun O. Liu from Johns Hopkins University achieved the first laboratory chemical synthesis of PatA, shortly after they discovered that it inhibits protein synthesis in human cells and is as much as 2,000 times more toxic to tumor cells than to healthy cells. Romo says researchers and pharmaceutical companies -- including two in Boston that have examined it as a possible chemotherapy agent -- widely view it as an attractive lead compound in the fight against cancer and an important tool for basic studies of mammalian protein synthesis.
Romo notes that PatA is but one example of the many intriguing possibilities in light of the current scientific community's broadening interest in natural products. He says this interest is in direct contrast to the attitude characteristic of mainstream pharmaceutical companies during the previous 10-to-15 years -- a mindset Romo says stems in large part from perceived disadvantages despite all possible and often proven medical advantages. In the past, the drug industry began shying away when organic chemists simply could not generate the required large quantities of small molecules using natural products in the same way they could with combinatorial chemistry methods. Extracting compounds with drug-development potential from natural resources also proved to be a tedious chore, given that they generally are difficult to obtain from their environments. To them, it was simply not worth the investment.
Enter LINCHPIN, which counteracts pharmaceutical companies' traditionally dismal outlook on natural products with the help of a new derivatization method known as "simultaneous arming and structure-activity relationship" (SAR) studies. This process enables researchers to determine which parts of a molecule are suitable for attachment of a cellular probe while at the same time attaching a "handle," thus arming the natural product for coupling to a probe that can be detected. Once these methods are applied to a given molecule, they can be retested by the collaborating lab to determine if these derivatized molecules retain their biological activity or not. The technique allows the LINCHPIN group, in collaboration with the initiating project scientists, to figure out how these molecules are affecting cellular processes using these probes.
Meanwhile, the lab also is taking a proactive approach to determining the potential of the compounds it is studying; namely, conducting very early preclinical studies to better determine the potential of the natural products and derivatives they are synthesizing. In one example, the group is using a Liquid Chromatography-Mass Spectrometry (LCMS) system, which analyzes mixtures of compounds and measures their mass to determine how long a drug lead will last in human blood serum -- critical information that represents a vital step in the drug-development process.
Romo predicts the exciting combination of more efficient derivitization methods and early preclinical testing of potential drug candidates might prove to be the perfect hot ticket needed to entice pharmaceutical companies to cash in by conducting further studies with these natural products or their derivatives prepared by LINCHPIN chemists.
"The fact that many pharmaceutical companies were moving away from natural products was something LINCHPIN was trying to address, and that's one of the ways the lab came about," Romo says. "We saw natural products as a very important class of compounds to go after as potential drug candidates. There is a niche for this that was missing."
It's not just the pharmaceutical industry that could gain from LINCHPIN's efforts. Romo hopes that establishing a central location for these new partnerships will lead to mutually beneficial outcomes for associated researchers' respective institutions -- sub-contracts from collaborative proposals, co-publications and future program projects that could inevitably lead to more grant rewards or other major federal funding. In addition to ideally enabling LINCHPIN to function as a self-sustaining facility, such resources would provide additional support for postdoctoral research associates like Assistant Director Dr. Jing Li as well as graduate students like Supakarn Chamni, who earned her Ph.D. in December 2011 as one of the first graduate students to develop new methodology for tagging natural products en route to actual natural-product probes for biological study which now are being used in the LINCHIN lab.
"It's been a good opportunity to build research connections and gain research knowledge from the LINCHPIN team and to realize that my work will be useful for drug discovery," Chamni says. "Furthermore, it's also a good place to learn advanced organic chemistry for natural products research -- molecules which can sometimes be quite sensitive to work with."
Beyond the traditional graduate and postdoctoral beneficiaries of academic research, LINCHPIN also features something for undergraduates -- an innovative "TAMU Undergraduate Minipharma" program in which a handful of undergraduates from diverse disciplines work together with LINCHPIN scientists to develop drug leads in some of the same ways they are developed in the pharmaceutical industry. In one current project focused on an unusual approach to cancer chemotherapy, two undergraduates were tasked with synthesizing enzyme inhibitors, another two were responsible for computer simulations of the enzyme inhibitor-enzyme complex, while a third pair conducted biological assays side-by-side with eminent Texas A&M biochemist and biophysicist Dr. James Sacchettini, one of LINCHPIN's many highly acclaimed affiliates.
"This is basically a pharmaceutical environment for teaching high-achieving undergraduates," Romo says.
Regardless of the project or constituencies it may benefit, Romo and his fellow LINCHPIN researchers have one common goal: to return natural products to their former glory.
"Natural products have a rich history of leading to drugs that help humankind, and so I am motivated to continue mining their rich information content -- thinking about how to make them in a practical manner, what they do inside diseased cells like cancer cells, how they are made in the producing organism, and pondering why they are there in the first place," Romo says. "[Is it] happenstance or [was it] planned?"
Watch an interview with Dr. Romo about LINCHPIN on You Tube:
Contact: Chris Jarvis, (979) 845-7246 or firstname.lastname@example.org or Daniel Romo, (979) 845-9571 or email@example.com
Answers in the Unexpected
Texas A&M University chemist Dr. Daniel Romo is using chemical synthesis to kick-start the fight against cancer and other human diseases, one natural product at a time, starting with Pateamine A, a compound that comes from the sea sponge Mycale sp., pictured here at 70 feet in Doubtful Sound, Fiordland. (Credit: Mike Page)
Jennings (foreground) and Li, working in the LINCHPIN lab.
Dr. Mingzhao Zhu, one of several postdoctoral research associates affiliated with LINCHPIN.
One specialty of the LINCHPIN lab is synthesizing cellular probes, which consist of a linker and a reporter tag synthetically attached to the original natural product. These cellular probes then allow biologists to figure out what the natural product is doing inside the cells and, ultimately, in the human body. (Credit: Mikail Abbasov, Romo Group)