Saturday, October 25, 2014

TGen

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inside This world-class facility, Gene sleuths are uncovering clues that could lead to cures for cancer.


Looking around the Translational Genomics Research Institute (TGen), you constantly get the sense you’re missing a geneticist’s inside joke. Step into this veritable shrine to DNA, and you’ll tread on tiles designed to look like
double helixes twisting down the hallways. If nature calls, you’re directed to the gender-appropriate restroom by colorful 3D blocks shaped like an X or Y chromosome.

Peek over a researcher’s shoulder, and you’ll likely see something that resembles a high-tech color wheel on their computer monitor: the human genome.

The esoteric decor is fitting for an institution that’s quietly unraveling the mysteries of the world’s deadliest diseases. Despite TGen’s total statewide economic impact of $137.7 million in 2010 and the fact it occupies a highly visible position in Downtown Phoenix, most people have no idea what goes on there.

Put simply, there’s a war on every floor: the brightest minds in medicine and science versus the most aggressive types of cancer and disease. The faculty at TGen features an elite crew of researchers, including pancreatic cancer expert Dr. Daniel Von Hoff; “biohunter” Dr. Paul Keim, a pathogen guru who serves on the federal government’s National Science Advisory Board for Biosecurity; Dr. John Carpten, a leading researcher in cancer genomics; and world-renowned geneticist Dr. Jeffrey Trent. There are twelve research divisions and about a hundred lab stations inside TGen, plus about 45 ongoing clinical trials at partner facilities. TGen has innumerable partnerships, which extend to just about any medical institution in Arizona, from the Mayo Clinic to Scottsdale Healthcare to Banner Health, and beyond, to universities and medical facilities across the country. They have even partnered with PetSmart in a program to research dog cancer.

They’re using the map of the human genome to chart a course toward their goals: to identify potential causes of cancer, discover preventative measures to decrease the risk of cancers, and find new and better treatments for cancer patients.

“TGen has been among the first in the nation to use genomic information for individual patient prediction, trying to customize a treatment,” president and research director Dr. Jeffrey Trent says. “We work on the worst type of breast cancer, the worst type of brain cancer, the worst type of skin cancer, the worst type of abdominal cancer, pancreas cancer. TGen tends to focus on trying to give hope where there is no hope.”

Scientists Get Into Your Genes
Dr. John Carpten leans in toward his computer monitor and points to a series of dark, spiky lines displayed on the screen. To the layperson, it looks like a static mess, an anorexic Rorschach test or perhaps a collision of line graphs run amok. But to Carpten, director of TGen’s Integrated Cancer Genomics Division, this storm of squiggles represents a powerful weapon in the war on cancer.

Carpten is showing us a partial representation of the human genome – specifically, the genome of a woman with triple negative breast cancer, one of the deadliest forms of the disease. Carpten’s been squinting at these chaotic-looking lines for hours now, like he’s intensely searching for a solution hidden in an intricate puzzle – which is exactly what he’s doing.

The human genome, stored on the 23 chromosome pairs that are embedded in the nucleus of almost every human cell, is the crux of TGen research. Dr. Trent says the information contained in the human genome is “basically a textbook of medicine,” and TGen’s pièce de résistance is human genome sequencing.

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Carpten likens genome sequencing to taking Leo Tolstoy’s epic novel War and Peace and writing out the definition for every single word – except that a 560,000-word tome falls far short of the human genome’s 3 billion base markers (i.e., the chemical molecules in DNA). “[It’s] a lot of little bits of information,” Carpten says. “And any little piece of information, if altered, can take that cell down a completely different path from a normal growth pattern or functional pattern it was destined for.”

Imagine our cell structures as a network similar to an electrical circuit. A disturbance in any point of an electrical network could alter the circuits below that point and change the intended result.

“Cells behave in a similar fashion,” Carpten says. “There are proteins that interact with different networks. Some of these networks tell a cell, ‘Okay, I want you to grow and divide ten times, and then don’t divide ever again. And you’re going to live for a destined amount of time, and then you’re gonna die off, and we’re going to replenish you with a fresh cell that’s going to do the same thing.’ And so you can imagine, if the signal to tell that cell to die is altered and the cell doesn’t die, now another one gets made, but this one didn’t die – and another, and another, until you have this build-up of cells, right?”

That’s cancer.

“A lot of times, what happens is, the initial change occurs at the beginning level, and the change in the DNA results in a change in the protein,” Carpten continues. “Change in the protein leads to a change in the cell, a change in the cell leads to a change in the tissue – disease. So that’s essentially it. We’re essentially trying to find that change in the genome that has led to the reason why this cell is no longer going down a normal growth path.”

Finding these abnormalities is like solving a genius-level version of the newspaper puzzle Hocus-Focus, in which you try to pinpoint the differences in two near-identical drawings. “What we’re doing is, we’re sampling all 3 billion bases of the genome, and we’re looking for those changes. And for each individual person, we have to sequence the tumor genome, and the person’s normal genome, and compare the two and say, ‘What has been acquired in the tumor genome? What’s different in the tumor genome from the person’s normal genome?’” Carpten explains. “And those changes are those that tend to provide us with information on 1) why the cell became a tumor cell, and 2) is it going to be a very aggressive tumor, versus an indolent form of cancer, and 3) those mutations or changes become vulnerabilities. They’re targets. We say, ‘Okay, the cancer cells have a mutation in this particular protein. Can we develop a small molecule, a compound that will target a specific protein? If so, we can kill the cancer cells.’”

One of the challenges of trying to fight cancer is the disease’s ability to mutate, even in the face of cancer treatment drugs. “It changes and adapts to try to survive in the environment or in the presence of that drug,” Carpten says. “So the tumor we sequenced up front may be completely different from the tumor sequence three years later.”

Ideally, TGen scientists sequence new samples from the same patient’s tumor over a span of time. “The more access to samples we have across different points in the landscape provide us more information on how to fight this fight,” Carpten says. “It’s a real war. It’s no different than a war. You set up a battle strategy, you put your troops in a certain place, and what does the enemy do? He adapts, right? And that’s how cancer is. People have given us a lot of grief about the ‘War on Cancer,’ but cancer’s smart.”

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Birth of a Biomedical Campus
Looking north through the windows of his sixth floor office, Dr. Jeffrey Trent sees a vast expanse of central Phoenix, sprawling all the way out toward the raggedy purple peaks of the Bradshaw Mountains. As president and research director of TGen, Trent has had this view since helping plant the facility in the heart of the city 10 years ago. The knee-high bookshelves that line the north wall of his office are filled with framed certificates and shiny commemorative plaques, including a photo of Trent with Arizona senator and melanoma survivor John McCain, and a framed graphical representation of the first sequenced genome TGen did in collaboration with Mayo Clinic back in 2010. 

TGen’s journey from idea to icon has been swift. Arizona lawmakers and voters had sought to make Phoenix a biomedicine mecca since at least 2000, when voters approved Proposition 301, which levied a .6 percent sales tax increase to fund education (the initial wave of revenue was partly used to build the Biodesign Institute at ASU). In February 2002, then-Arizona Governor Jane Hull appointed an Arizona BioInitiative Task Force to raise enough money to attract the International Genomics Consortium (IGC) to Phoenix and establish TGen. At that time, there was nothing quite like it – and there still isn’t. Many universities have genetics programs, and there are a handful of other genome research institutes nationwide, but “TGen is the only medical research organization solely devoted to molecular-based medicine,” according to TGen COO Tess Burleson. Five months after Governor Hull’s announcement, $90 million had been raised by public and private sources, including $10 million from the Flinn Foundation and $5 million from the Virginia G. Piper Trust.

The fast financing and concerted dedication drew Trent (then-director of intramural research at the National Human Genome Institute in Bethesda, Maryland) back to his native Phoenix. At that point, Trent – a twin who says he was interested in medicine from birth – had already established himself as an expert in the field of human genetics, having studied in Indiana University’s acclaimed genetics program (graduated scientists include James Watson, who received the Nobel Prize in 1962 for his role in discovering DNA’s double-helix structure).

“The decision process involved a community engagement that was second-to-none,” Trent says. “I looked at a couple different models for how to frame TGen, and how to really pull together a genomics research institute. The majority of those would have been linked to a single institution. And this was an opportunity to put something in place in Phoenix 10 years ago, [when there were few] existing links in the biomedical services.”

In June 2002, Trent announced he would relocate the IGC to Phoenix and take the helm of TGen, which officially launched that month, sans an official structure. The City of Phoenix donated land for construction of the TGen facility, and architecture and engineering firm SmithGroup began working on its design. Construction of the $46 million, 173,000-square-foot TGen building was completed in 18 months.

Trent’s presence drew more elite researchers to TGen, including Dr. Paul Keim, current chair of microbiology at Northern Arizona University and director of the Pathogen Genomics Division at TGen North in Flagstaff. “In 2003, I didn’t see the future for genomics in the state of Arizona, and I had offers on both coasts, and was ready to go. But when Jeff Trent came…it was a game-changer for me, and it made Arizona a place where I could have access to cutting-edge technology,” Keim says. “This technology’s always been pushed by the human genome, and infectious disease folks like myself are just grabbing ahold and hanging on as it sweeps us into the future. That’s what Jeff Trent did when he came to Arizona. He just brought the technology and moved Arizona ahead decades.”

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Support for TGen as the foundation of Arizona’s burgeoning bioscience industry has been rapid and enduring. The company’s board of directors reads like a who’s-who of Arizona business and politics, and includes Stardust Companies CEO Jerry Bisgrove, Arizona Diamondbacks Managing General Partner Ken Kendrick Jr., Biltmore Bank of Arizona founder Richard J. Lehmann, PetSmart executive chairman Phil Francis, Arizona Governor Jan Brewer and Phoenix Mayor Greg Stanton (TGen reserves automatic spots on its board for the governor and mayor).

TGen’s scientific progress has been as swift as its institutional growth. Scientists worldwide began trying to map the human genome in 1990, with the launch of the international Human Genome Project, initially spearheaded by the Office of Biological and Environmental Research in the U.S. Department of Energy’s Office of Science. The goal was to find the sequence of chemical base pairs that comprises DNA.

Trent was involved in sequencing the first genome at the National Institutes of Health’s National Human Genome Institute, and says that first genome map took 10 years and cost $3 billion.

“It took the whole world’s involvement. We shamelessly patted ourselves on the back because we were ahead of schedule and under budget for a government project,” Trent recalls. “It was supposed to be 13 years; it took 10. It was supposed to be $5 billion; it only took $3 billion. But today, what took us 10 years and $3 billion dollars takes us less than 10 days and only about $30,000. It’s an incredible reduction in cost, and an even more incredible [increase] in the speed.”

 

Billions of Bases, Billions of Bytes
Some of the steps in sequencing the human genome at TGen are performed in the Neuro Genomics Lab, which doesn’t look that different from a high school science laboratory – if the high school were operating a hundred years in the future and money were no object.

Lab stations are arranged in rows, crowned by metal shelves filled with various tubes, boxes of gloves, and books with titles like Principles of Neuro Science and Bioinformatics: Sequence and Genome Analysis. Glass beakers of various sizes line the shelves at the end of each station. Researchers in white lab coats carry clipboards and equipment from one place to another, while exotic machines pulse and beep in corners.

Here, lab workers extract DNA from tissue samples (donated by doctors and diseased patients) to prepare them for sequencing, analyze proteins, and feed information through supercomputers capable of quickly processing more than 6 billion bits of information. One such machine, called the HiSeq 2000 Illumina, looks like a futuristic mini-fridge with a jumbo computer monitor attached to the side. There are a handful of these machines in the Neuro Genomics lab, each labeled with a name so researchers can tell them apart. Some are named after characters in the Peanuts comic strip, others after characters on the TV show South Park. Upstairs, in the Proteomics lab, there are more high-dollar machines, some of which were made especially for TGen’s labs and do not exist anywhere else.

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Photos - Clock-wise from top left: A blue spike on screen indicates genetic risk factors in pug dogs; bioinformatician Jason Corneveaux, who helped conduct the pug study; an electrophoresis system for protein separation; lab worker Mari Turk examines protein reactions.

  
Massive computing power is necessary when trying to study 3 billion bases of a human genome. A single experiment at TGen easily produces 30 terabytes of data, roughly the equivalent of an iPod containing 15 million songs. The total storage capacity within TGen’s computer room is more than 1,000 terabytes – 100 times the amount of information in the printed collections of the U.S. Library of Congress.

TGen has a high-speed fiber-optic connection with the Saguaro 2 supercomputer on the ASU campus in Tempe. It’s one of the fastest supercomputer links among life-science facilities in the nation, and data sets containing trillions of bits of DNA information can be transferred in just a few hours. The data encryption technology TGen uses was designed for military applications.

In November 2011, computing giant Dell announced it was partnering with TGen and the Neuroblastoma and Medulloblastoma Translational Research Consortium to help find new and better treatments for pediatric cancers. Dell donated its “cloud computing” technology to provide TGen with the computing power to increase its gene sequencing capacity by 1,200 percent.

“[These technologies are] based on imaging and lasers and fluorescents, and again, we can turn around a genome in about two weeks for about $10,000. But the throughput – the amount of sequence we can generate based on a cost-per basis – is actually exceeding Moore’s Law now,” Dr. Carpten says, referencing a long-term computing trend in which the number of transistors that can be economically placed on an integrated circuit doubles every two years. “And so we’re almost pretty sure that we’ll be able to do a whole genome in three hours for about a thousand bucks by the end of this year.”

That’s an exciting prospect for Dr. Trent, too, but ultimately a small piece of a huge puzzle. “What we firmly believe is that interpreting the information from the genome is going to be the next great textbook of medicine, and is likely to take us a hundred years to get the full secrets. We’re just beginning the knowledge and interpretation of what we’ll learn over the next decade,” Trent says. “I think it’s one of the most exciting times for a new scientist to start, to really extend that into changing the lives of patients. It’s an incredibly exciting time to enter medicine and science.”

Expanding, Contracting
“We’re like Switzerland. We work with everybody.”

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Machines in the Neuro Genomics lab at TGen (left); research assistant Lori Phillips prepares DNA samples for sequencing (right).


Tess Burleson, chief operating officer at TGen, is discussing the organization’s plethora of partnerships. One of the biggest is their Phase 1 clinic at the Virginia G. Piper Cancer Center at Scottsdale Healthcare, where cancer patients can receive new or alternate treatments based on information in their genome. TGen also works closely with the Mayo Clinic, University of Arizona, and Arizona State University. “There’s not a clinic or physician that we wouldn’t work with, if they had an interest in aligning with what we can provide as a service,” Burleson says. “We tend to be available to any clinician who feels like what we do can benefit their patients.”

In 2007, TGen opened a facility in Flagstaff called TGen North, a pathogen-genomics and biodefense research facility operated in collaboration with Northern Arizona University. That same year, TGen teamed up with the Biodesign Institute at ASU and Lee Hartwell (a 2001 recipient of the Nobel Prize in Physiology or Medicine) to develop a multi-million-dollar proteomics program to study the structures of proteins, including a state-of-the-art proteomics lab at the TGen facility. In 2008, the government of Luxembourg committed $200 million to TGen for cooperative research projects involving the Partnership for Personalized Medicine (which shares researchers from TGen and ASU’s Biodesign Institute) and recently appointed Dr. Trent Foreign Trade Counselor of Luxembourg in the United States. And in 2010, the Arizona Legislature gave the green light to use bonds issued by the Arizona Board of Regents to construct a new Health Sciences Education Building on the Phoenix Biomedical Campus, which was still under construction at press time.

It’s partly the way TGen plays well with others that makes it so profitable for Arizona. Tripp Umbach’s analysis showed TGen’s operations – including business spinoffs and commercialization – in 2010 generated $10.1 million in state tax revenue, supported 1,124 full-time jobs (directly and indirectly), and produced $25.04 for every $1 invested. Tripp Umbach predicts that by 2015, TGen operations including spinoffs and commercialization will support 3,723 jobs, generate $21.1 million in Arizona tax revenue, and produce an annual economic impact of $258.8 million. Numbers like that make TGen “one of the nation’s more successful economic engines in the biomedical sector,” according to Tripp Umbach President Paul Umbach.

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Such sentiments are echoed by in-state luminaries like Arizona Cardinals president Michael Bidwell, who has said, “TGen is one of the state’s premier medical research and economic assets, and is a standard-bearer for promoting everything that is positive and forward-looking about Arizona.”

Treatment options for many devastating diseases are expanding thanks to the work of researchers at TGen. In the past year alone, the institute has launched clinical trials for potential new drug treatments for breast cancer, non-small-cell lung cancer, pancreatic cancer, and a uniformly fatal cartilage cancer called chondrosarcoma. Researchers have also identified compounds that could slow down Alzheimer’s disease, and gene mutations that lead to lung cancer in nonsmokers. In February, the FDA gave expedited approval to a new skin cancer drug called Vismodegib that had been tested for the first time anywhere five years ago at Scottsdale Healthcare, as part of TGen’s clinical trials. There’s also an ongoing program to research disease in dogs to inform our knowledge of similar diseases in humans. 

That initiative, the Program for Canine Health & Performance (PCHP), is part of the Canine Hereditary Cancer Consortium (CHCC), and is conducted by TGen and the Van Andel Research Institute (VARI) in Grand Rapids, Michigan, with support from Hill’s Pet Nutrition and Arizona-based PetSmart. There are many illnesses mutual to dogs and humans, Dr. Trent says, including cancer, Alzheimer’s, epilepsy, and Lou Gehrig’s disease. To date, the CHCC has collected more than 10,000 canine biospecimens for study.

In the spring of 2011, researchers at TGen published a study in the Oxford Journals’ Journal of Heredity showing two genetic risk factors in the chromosomes of pug dogs that may be linked to a canine disease called NME. NME, or necrotizing meningoencephalitis, is a disorder similar to some types of multiple sclerosis in humans. Additional study of NME in dogs could uncover clues about the causes of MS in people.

“[The canine research program] is incredibly relevant to what we’re doing on the human side. It’s been one of those great success stories of an Arizona-based company, PetSmart, aligning with TGen to try to make a difference for both dogs and man,” Trent says. “This is a great story of man’s best friend helping give us the information to help support the trials we’re doing.”

Six out of 10 dogs die of cancer, Trent says, and some breeds are particularly susceptible to certain cancers. “Because we know that in advance, can we use this genetic information, sequence the dog genome the same way we did the human genome, and identify changes in the dog that might help us understand that?” Trent asks. “And these are also cancers that we find in people – like melanoma. We do a lot of work in regards to that.”

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In with the New
Dr. Trent is looking through his office windows again, down at the grounds of the Phoenix Biomedical Campus. The peaks of the Bradshaw Mountains still peek at him in the distance through the north windows, but when he turns and looks out the east-facing windows, his view is quite different.

Here, he sees a construction zone: the site of the soon-to-be-completed Health Sciences Education Building, a 268,000-square-foot structure wrapped in shiny copper that beams sunshine back into Phoenicians’ eyes with glaring enthusiasm.

The $129 million building provides a component vital to the continued growth of the Phoenix Biomedical Campus. The building will allow the University of Arizona’s College of Medicine in Phoenix to accommodate at least 110 students per class, compared to its current capacity of 48 students per class.

Having a branch of the U of A College of Medicine in Phoenix is a pretty big deal. Until the College of Medicine set up its satellite school on the biomedical campus downtown, Phoenix was the largest city in the nation without an allopathic medical school. Once construction is completed (projected for August), the new Health Sciences Education Building will also house students from ASU’s College of Nursing and Health Innovation, Northern Arizona University’s Allied Health Program, and the University of Arizona’s College of Pharmacy.

It likely won’t be the last new foundation laid around TGen – at least, Trent hopes it won’t be, despite his dwindling view.

“We’re ready for more buildings,” he says, smiling. “I’m happy to get rid of my view and replace it with the backside of another large medical building, as soon as they’re ready to do that.”

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From left: Dr. Paul Keim, director of the Pathogen Genomics Division at TGen North in Flagstaff. • The TGen building sits in the heart of the Phoenix Biomedical Campus.

 

 

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