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Promise and Progress - The Science of the Invisible

Leading the Way Fall 2009 Winter 2010

The Science of the Invisible

By: Valerie Mehl
Date: December 1, 2009

Scientists Use New Technology to Reveal the Inner Workings of the Cancer Cell

“What is taking so long?” It is a question frequently asked by a wearypublic that hears almost daily of new cancer discoveries yet continues to live in a world wherecancer remains one of the deadliest diseases.

THE ANSWER, say experts, is technology. Cancer is very complex. It is a disease of many broken parts. In order to fix the broken parts, researchers need to understand them in detail. Yet these parts, contained within the DNA of a cell, are so small they cannot be seen even with the strongest of microscopes.

But, a new technology called next generation sequencing is now allowing researchers to see inside the cancer cell in a way that was not possible before. It is speeding the pace of discovery and already yielding new diagnostic and therapeutic tools to fight cancer.

In the past, it could take decades of research—an entire career—for a scientist to identify and isolate just one cancerrelated gene hidden within the DNA of a cancer cell. This
painstaking and difficult research has been frequently equated to finding the proverbial needle in the haystack. Well if that’s the case, then experts say next generation sequencing is the technology that can quickly look at every piece in the stack and tell whether it’s hay or a needle. As a result, cancer research that used to take decades can now be completed in months.

Kimmel Cancer Center researchers, who have consistently led the field in cancer gene discoveries, are poised to use the new technology to speed their progress against the disease.

Unprecedented research led by Bert Vogelstein more than two decades ago revealed cancer as a genetic disease, caused by mutations to growth promoting and growth suppressing genes. Stephen Baylin uncovered epigenetic alterations, cancer-initiating mistakes made to the way genes are packaged within the cell. Their discoveries became the most frequently cited in the field; yet, amazingly, much of their work was accomplished without the benefit of today’s technology.

It is this example of ingenuity and progress, in the face of what seems like insurmountable odds, that leads many to believe that Johns Hopkins—with its convergence of some of
the most brilliant minds in science, medicine, and engineering—is best positioned to use this technology to benefit people.

The Instrument That Sees
Like many of the great advances in cancer that occur beyond what the eye can see, the box-like machine and its accompanying computer are rather unassuming. One could never imagine, simply by looking at it, the magnificence of what it does or its potential to revolutionize cancer therapy.

The technology harnesses into one powerful piece of equipment the most advanced technology in imaging, optics, molecular biology, chemistry, computer science, and engineering to simultaneously sequence millions of gene targets. Try to imagine a pathology slide with 200 million things on it. It is virtually impossible, but this sophisticated equipment is able to do it, quickly seeing each of these 200 million elements and
differentiating one from another.

Since 1965, one trillion of the base pairs that form our DNA and that of other organisms have been sequenced and stored in public databases. With next generation sequencing, what took a half century can now be completed in less than one year in a single, modest-sized laboratory.

The instruments don’t come cheaply, however. One next generation sequencing instrument costs about $500,000. The computers that collect the data run another $200,000. As a result, the Kimmel Cancer Center currently owns just one, located in the Vogelstein laboratory and donated by the Ludwig Fund. An additional two machines are being leased from the manufacturer to create a next generation sequencing laboratory that will make this crucial technology available to more Kimmel Cancer Center researchers.

It has become essential to ensuring the pace of cancer research. “There are six billion bases in the human genome and five separate changes may be needed for cancer to develop. We will simply not find all of these critical changes using small-scale methods,” says Vasan Yegnasubramanian, Co-director of the Center’s new next generation sequencing lab.

While high up-front costs hinder widespread availability to the technology, it has dramatically slashed the overall cost of genetic research. In 1985, the cost of genetic sequencing was approximately $10 per base pair. Currently, with the advent of next generation sequencing technology, it has plunged to 1/1,000 of one cent per base pair and is still declining.

“In five to ten years, people could potentially have their entire genome sequenced for what it costs to have routine bloodwork done,” says Yegnasubramanian. It is this limitless
potential that causes many experts to say that the real challenge is no longer in sequencing genes but in knowing what to do with the information.

“It opens the door to questions of extraordinary scale,” says Yegnasubramanian. He smiles broadly when he discusses the possibilities. It is clear that he is genuinely excited about the potential and what it could eventually mean for cancer patients. “There really are no boundaries to what we can learn now,” he says. “Time, imagination, and money are the
only limitations.”

The Mathematics of Cancer
If the DNA from one cell was stretched out end to end, it would be nearly two yards long, yet it is tiny enough to fit inside a single cell. Despite decades of discovery, what we
don’t know about our DNA far exceeds what we do know. To use a football analogy, what we know would take us to the two-yard line, but next generation sequencing is pushing us the remaining 98 yards into the exploration of areas of the human genome that have never before been studied. The goal is new therapies specifically targeted to the unique genetic characteristics of each person’s cancer.

Working with Yegnasubramanian and taking charge of the daunting analysis is computational biology expert Sarah Wheelan. She is undeterred by the amount of biological data this technology produces—more than 80 billion pieces of information
per study—and the knowledge that it exceeds the capacity of even the most sophisticated computers. Scientists have never before seen this amount of data, but it is a challenge that seems custom made for her. Wheelan has taken on math calculations for fun that most people would not even begin to know how to solve. She once calculated that the DNA from all 60,000 Johns Hopkins employees stretched out end to end world reach to the edge of our solar system and back.

The ability to make sense of the billions of data points generated by next generation sequencing is probably more about human ingenuity than hardware, and it’s where Kimmel Cancer Center researchers like Wheelan are already ahead. “In five to ten
years, it will be commonplace to sequence every cancer genome,” says Yegnasubramanian. Real progress, he says, will then be measured by who is best able to interpret and use the massive amounts of data to make a difference in patients.

Like a card catalog system in a library, the technology helps researchers understand how a cancer cell is organized and how the cell changes its organization. A genome
is not sequenced in one big piece, but in tens of millions of small chunks that have to be matched up to where they came from. A computer cluster, or group of linked computers working so closely together that they essentially form one super computer, then explores
these sequences, finding genes that are over expressed and under expressed. Because the genome sequence is just one layer of the cancer cell’s complexity, researchers like Wheelan must then examine the interplay between genetics (alterations directly to the DNA) and epigenetics (alterations to the way DNA is packed into a cell). Finally, and perhaps the most pressing challenge is to figure out whether or not any of these things make a difference in cancer—what is significant and what is not.

“Think of a sweater,” says Wheelan. “Imagine if you could unravel the sweater thread by thread, put it in a dryer, and have it come out whole again,” she says. “That’s what this technology does for us. It allows us to unravel the human genome and gives us back something that makes sense.”

Wheelan has received a grant from the Johns Hopkins Provost to start a computational genomics center, and her interdisciplinary team is hard at work on innovative analysis
techniques that complement the groundbreaking experimental work being performed at the Kimmel Cancer Center and throughout Hopkins. “These collaborations are critical to
progress in fighting cancer,” says Wheelan.

While other research institutions have been stymied by the immense amount of data, she has put the Kimmel Cancer Center ahead developing solutions and technology on the fly.
With billions of measurements that can be done for each tumor sample, the real skill comes in sifting through the data to determine what needs to be kept and looked at, and what can be put aside. It is the first time since the development of computers that biological data has surpassed the computer’s ability to handle it. “We considered this going in and began developing analytical tools,” says Wheelan. She is getting some
advice from particle physicists at the Johns Hopkins Applied Physics Laboratory, the only other people on the planet that work with data sets this large.

“That is what is so special about this place,” says Kimmel Cancer Center Director William Nelson. “There is no other institution where you can pick up the telephone and get the leading expert in a particular field, and pick his or her brain for two hours to help
solve a problem. I’ve spoken to my colleagues at other places. This kind of collaboration does not happen elsewhere.”

The Most Complex Disease
Every cancer is unique. As cancers develop over time, multiple genes are involved and contributing factors, such as inflammation and environmental assaults, help create a
cellular environment for tumor progression. This diversity is what makes cancers so hard to treat.

The hope is that the new next generation sequencing technology and the computations that accompany it will help make sense of this complex process that leads to cancer.

“It allows us to understand individual cancers at a level that was not possible before,” says leading nextgeneration sequencing expert Victor Velculescu.

It was the renowned team of Velculescu, Vogelstein, and Kenneth Kinzler, who, with fewer resources and fewer people, became the first to map the cancer genomes of colon,
breast, pancreatic, and brain cancers. On their heels were larger and better funded teams at the National Institutes of Health and the UK’s Wellcome Trust Sanger Institute.

This is one example where ingenuity in fact beat hardware. “Because of the great minds we have working together in the Kimmel Cancer Center, we are able to do more with
less and keep a rapid pace of discovery,” says Center Deputy Director Stephen Baylin.
He worries, however, that his investigators will not be able to maintain this pace without greater access to this leading technology.

It’s More About the Genes than the Organ
Baylin knows it is key to revealing the unique genetic fingerprints of cancers and gaining a new understanding of the disease.

Traditionally, cancers have been defined by the place in the body where they occur, and treatment decisions have been guided by this principle. Genome sequencing has led scientists to believe that how a cancer behaves and responds to treatment is more about its genetic profile than its physical location.

Kimmel Cancer Center experts expect the paradigm to begin shifting with clinical trials for new therapies directed at groups of patients whose cancers have similar genetic and epigenetic characteristics rather than similar locations in the body.

Using the new knowledge to organize clinical trials, so that drugs are being tested in patient populations based on like genetic traits in their cancers instead of like locations of their cancers, will quickly reveal if a drug works before millions of research dollars
are spent, says Nelson.

In their survey of the colon cancer genome, Velculescu and team revealed a complex landscape for cancer containing a variety of different and less frequently occurring mutations that vary from patient to patient. These new findings explain why seemingly similar cancers—originating in the same organ—often respond very differently
to therapy. “Though cancers from different patients may look the same, genetically they are very different,” says Velculescu.

Wheelan says that as the new technology is used to look at the genomes across all tumor types, patterns will begin to develop that will help experts target therapies to the genetic and epigenetic defects that cause the cancer to originate, grow, and spread.

The biggest promise lies in those cancers, like lung, brain, and pancreatic cancers, where current therapies are largely unsuccessful. Investigators believe this type of research will lead them to a genetic explanation for how these tumors evade current treatments. With this information in hand, they can begin to find each cancer’s genetic weakness and go after it.

Already the team’s genetic blueprint for brain cancer has revealed mutations in two genes, IDH1 and IDH2 that represent a clinically and biologically distinct subtype of the cancer.
“New treatments could be designed to target the enzymatic activity that is altered by these mutations,” says Velculescu. He says that discoveries like these will be easier to make in the future using next generation sequencing technology. “No one would have ever suspected this mutation in this cancer,” says Velculescu. “We wouldn’t have found it without this tool, and now we know it is key to prognosis and treatment response.”

Likewise, investigators performed a personalized genome sequencing of a patient with a hereditary form of pancreatic cancer and uncovered the mutated gene responsible for initiating the patient’s disease.

 Imagine the Possibilities
Genetic research has uncovered mutations that have led to new screening tests for cancers, to new cancer therapies that target malignant cells while leaving normal cells
unharmed, and to ways to predict patients’ responses to particular drugs.

Investigators have found that mutation to a gene called K-ras makes patients’ cancer completely resistant to certain targeted therapies. With one month’s treatment with the
targeted drug Erbitux, for example, costing $16,000, this information can spare patients unnecessary treatments and costs. “There is no point in giving a costly drug that
science proves will not work,” says Velculescu. “This technology allows us to be smarter about identifying which patients will benefit from targeted therapies.”

In a market where there are 750 new drugs in clinical trials in each year—approximately 57 drugs for each known target—with nearly $1.5 billion spent per drug and a 95 percent
failure, the information next generation sequencing can provide is truly priceless, Nelson says.

And, it doesn’t stop there. Think of prostate cancer, Wheelan says. Despite 30 years of
research, recent data calls into question the value of population-wide prostate cancer screening. Some argue that it has led to more surgery, more unpleasant side effects, but notsaved more lives. Wheelan believes that next generation technology could lead to better tests that will allow investigators to compare tumor samples from many patients
and pinpoint the genetic signature that makes one prostate cancer more  lethal than another. With this information, clinicians will be able to differentiate tumors that must be
treated from those that could be monitored over time. This then helps accomplish the real goal, not just better detection of prostate cancer but also better outcomes.

Experts also say the technology makes preventing cancer, what many of them refer to as the only real cure, realistically attainable. “As we begin to understand more and more the
genetic patterns of cancer, we could potentially find something in a person’s genome that tells if and when a person is likely to develop cancer,” says Wheelan. Similarly, she says, observing the genomes of healthy people over time could help researchers understand what exposures and behaviors cause the gene alterations that lead to the development of cancer. Acting before a person develops a cancer ultimately saves both lives and money.