October 2010 Clinical Laboratory News: The Transformation of Medicine

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October 2010: Volume 36, Number 10

The Transformation of Medicine
Labs Key to New Paradigms

By Genna Rollins

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Tackling an emotionally, financially, and physically draining disease poised to exact a huge toll on society in the coming decade. Harnessing the power of the most sophisticated biological, analytical, and mathematical constructs to understand wellness and disease parameters for individual patients. Using cutting-edge molecular science to reprogram cells and bring personalized and regenerative medicine closer to reality. These were the visionary concepts put forward by plenary speakers at the 2010 AACC Annual Meeting, held July 25-29 in Anaheim, Calif. The three speakers, Leroy Hood, MD, PhD, James Thomson, VMD, PhD, and John Trojanowski, MD, PhD, projected a future in which laboratory medicine will play a vital role in transforming healthcare and improving patient outcomes.

“You’d have to be very narrow and prejudiced indeed to say that the complete human genome sequences of patients aren’t going to provide transformational opportunities, both for prediction and prevention,” Hood observed. “Diagnostics are going to be key.”

A New Paradigm of Healthcare

What do you get when you toss together a systems approach to biology, emerging nanotechnology, and powerful computational tools? In Hood’s view, these are the key ingredients of what he calls P4 medicine, a new paradigm that incorporates analysis of vast data inputs to consider the complexity of biological systems and their responses to wellness and disease, in aggregate and for individual patients. “Medicine has become an informational science, and my view of medicine is one that is information-based and data-driven,” he explained. “In the future, each patient will be surrounded by a virtual cloud of billions of data points and the question will be, how can we use that complexity to find parameters for wellness that are unique to each individual?” Hood is co-founder of the Institute for Systems Biology (ISB), a research institute dedicated to the integration of technology, computation, biology, and medicine.

Hood believes the P4 approach—predictive, personalized, preventive and participatory medicine—will drive the health- care system in the 21st Century, and he sees it as nothing short of revolutionary. “Many people don’t understand technology, but it’s what drives all of science. That’s why the advance of science is often thought of as being terribly incremental—and that’s true when technology isn’t changing too rapidly. But today it’s changing enormously quickly. We’re seeing exponentially higher throughput, more accurate data, and costs being driven down,” he explained.

Leroy Hood, MD, PhD, says the emergence of P4 medicine 
will revolutionize the healthcare system in the 21st Century.

A Mere Drop of Blood

Hood envisions that within 10 years, most everyone will have had a complete genomics analysis run at a reasonable cost. This information will enable a data mining of sorts that will provide a clear picture of health and disease for each individual, effectively shifting the focus of medicine from disease to wellness. On top of that, he sees a time when biannually, patients will provide a one-drop blood sample from which about 2,500 protein measurements will be taken, and these also will be used to assess health as opposed to disease for 50 major organ systems.

If this seems pretty far removed from today, Hood pointed to several projects ISB has underway that are planting seeds to achieve the P4 medicine model. Scientists at ISB recently completed an entire genome sequence for a family of four. This effort identified 230,000 new rare variants within the family and enabled investigators to create a precise recombinant map. “That gave us exactly the haplotypes of the parental chromosomal regions that conjoin together to make up the chromosomes of the children,” he explained. “What was fascinating is that about 70 percent of these recombinations fell in hotspots of recombination, and that has important implications for genetics.”

ISB researchers also have been studying prion disease in mice, analyzing its behavior as a network from a state of wellness through neuronal degeneration. The first set of analyses involved nearly 50 million data points. “This required creation of entirely new computational and integrative methods for dealing with a significant amount of data,” said Hood. The researchers also employed subtractive biological analyses to address “absolutely overwhelming” signal-to-noise problems. Hood believes this type of analysis can help investigators understand how biological networks become perturbed, and to eventually develop interventions to modify disease progression in humans.

In addition, ISB scientists have a goal to create within the next few years mass spectrometry assays for about 20,000 human proteins. Already they have developed such assays for 97% of yeast proteins, according to Hood.

Overcoming the Skeptics

ISB is beginning to tie the themes of its work together in a pilot project with Ohio State University Medical Center. “With lung cancer we plan to develop very early diagnostic markers and be able to stratify patients into different types so we can match them with appropriate drugs,” Hood explained. “In wellness, we hope to develop molecular and cellular parameters for evaluating each individual’s wellness status and use that to optimize behaviors to achieve greater wellness.”

This effort will be essential to moving the P4 medicine paradigm forward, according to Hood. “Scientists are trained to be inherently skeptical, cynical, and conservative, and they don’t feel comfortable with new ideas, so you just have to overwhelm them with success,” he observed.

As P4 medicine gains ground—an eventuality about which Hood is utterly confident—it will transform the entire healthcare landscape. “This will force every sector of healthcare to rewrite business plans in major ways,” he predicts. Laboratories will be part of this sweeping change. “My own feeling is that specialty diagnostic companies will emerge that have fine-tuned technologies that enable us to do what can’t be done today. There’ll be real opportunity for economic advances for these new companies,” said Hood.

Stem Cell Therapy Coming of Age

Pioneering stem cell researcher Thomson gave a compelling presentation about developments in and the promise of stem cell research in transforming medicine. The first scientist to isolate and culture an embryonic stem (ES) cell line in 1998, Thomson is the John D. MacArthur professor and director of regenerative biology at the Morgridge Institute for Research at the University of Wisconsin.

In 2007, his lab made history again by deriving eight new cell lines from human skin cells aided by four transcription factors. Like ES cells, these induced pluripotent stem (iPS) cells are capable of differentiating into any of the 220 cell types in the human body and proliferating indefinitely. However, they do not carry the same ethical, legal, or political controversies that surround ES cells.

James Thomson, VMD, PhD, presented his research on human-produced 
pluripotent stem cells and potential medical applications.

A Profound Change

The remarkable achievement of creating ES and iPS cell lines will open wide the doors of scientific discovery in ways that can’t even be foreseen right now, Thomson predicted. A comparable situation existed with the advent of recombinant DNA research in the 1970s. “Everyone knew that DNA was really important, but no one got the details right. We thought gene therapy was going to be easy, and we’re 30 to 40 years into it now and there’s no gene therapy to speak of. It profoundly changed everything, but the specifics were not accurate,” he observed.

Thomson also suggested that the breakthroughs made by his and other labs would pick up the pace of discovery in the field.

“A relatively small number of genes allowed us to do this, and it’s clear the work has implications beyond making the functional equivalent of human embryonic stem cells,” he indicated. “My sense is that things are going to move forward even faster now.”

Many Challenges Ahead

Even as the field advances rapidly, Thomson cautioned that a number of challenges still need to be worked out for both ES and iPS cell-based transplantation therapy. For example, researchers need to be able to reliably make the type of cells of interest, such as neurons or hematopoietic cells. Concerns exist as well about whether stem cells introduced into a patient’s body can provoke an immune rejection response.

In 2009, Thomson’s lab tackled a key safety concern associated with viral vectors, the method he used initially to deliver genes into skin cells in order to make iPS cells. The concern was that iPS cells created by this approach carried residual genetic material that could have triggered mutations in the induced cells. However, Thomson successfully used plasmids to introduce genetic material into the target cells. These circles of DNA that can replicate, but lack the complexity and efficiency of chromosomal DNA, can be engineered to introduce genetic material into cells and then be subsequently eliminated, thereby creating a line of iPS cells free of exotic genetic material. “We believe this was the first time human-induced pluripotent stem cells have been created that are completely free of vector and transgene sequences,” said Thomson. “It’s another important step along the way toward developing cells in sufficient quantity and quality to explore the possibility of human therapeutic use.”

Edging Towards Everyday Use

As Thomson’s lab continues its groundbreaking work, he looks forward to the practical application of stem cell therapy in areas such as drug discovery and regenerative medicine. The hope is that stem cells can improve the drug development process by helping researchers identify candidate compounds that are likely to be effective in specific patients. “If you already know what population responds in a certain way to a drug, you can tailor it better to different populations. It’s not easy to manufacture drugs in a way that’s tailored to particular parts of the market. This will allow that to be done in the future,” Thomson explained.

Already, several promising treatments based on stem cell therapy have been announced, and at least two received Food and Drug Administration (FDA) approval. For instance, in July, FDA approved the first-ever clinical trial in humans for an ES cell-based therapy that has worked in mice. This therapy, based on one of the cell lines Thomson developed in the 1998, will be used to treat patients paralyzed because of severe spinal cord injuries.

These developments are but the start of many exciting and groundbreaking discoveries ahead, according to Thomson. Stem cell therapy “is a very powerful, pervasive, enabling research tool and where creative people will take that, I have no idea. But I would be shocked if these cells aren’t found to be important 10 to 20 years from now,” he said.

Unlocking the Mystery of Alzheimer’s Disease

Trojanowski, recipient of AACC’s 2010 Wallace H. Coulter Lectureship Award, painted an exciting and optimistic portrait of future diagnostics and treatments for Alzheimer’s disease, which some consider the disease of the 21st Century owing to the fact that people are living longer than ever before. “We’re in the midst of a longevity revolution. There’s been a nearly doubling of life expectancy over the past century,” he explained. “From the time Dr. Alzheimer made his initial presentation about the disease in 1906, people thought it was an odd disorder and certainly didn’t appreciate that it would become epidemic 100 years later.”

The ‘silver tsunami’ of baby boomers who will start turning age 65 in 2011 will escalate the incidence of the already prevalent neurodegenerative disorder. An estimated 13 million people in the U.S. will have Alzheimer’s disease by 2025, up from about 5 million today. However, treatments that would slow the disease by even 5 years would decrease both the prevalence of and costs associated with the condition by about 50% by 2050, according to Trojanowski. He is co-director of the Center for Neurodegenerative Disease Research and William Maul Measey-Truman G. Schnabel, Jr. MD professor of geriatric medicine and gerontology at the University of Pennsylvania in Philadelphia.

Slowing down the disease is what researchers are striving for, and after years of investigation, Trojanowski finally believes it’s about to happen. “When I first started working on Alzheimer’s disease in the 1980s, I thought it would be 100 years after I was dead that people would be having conversations about the tremendous research focused on the disease, but the advances of science have been spectacular in the last 30 years,” he said. “We’re within striking distance of having biomarkers that can ‘go live’ in clinics, and within striking distance of having disease-modifying therapies.”

“We’re within striking distance of having biomarkers 
that can ‘go live’ in clinics, 
and within striking distance of having disease-modifying therapies,” 
said John Trojanowski, MD, PhD.

A Landmark Investigation

Trojanowski’s lab has been on the forefront of Alzheimer’s-related research, and is the biomarker core lab for the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a landmark, 6-year, $67 million clinical trial aimed at studying changes in cognition, brain structure and function, and biomarkers in elderly controls, subjects with mild cognitive impairment, and subjects with Alzheimer’s disease. Although the first phase of ADNI just concluded in September, the trial already has made significant contributions to the field. In Trojanowski’s view, one of the most notable has been standardization of procedures and analytics involving collection and processing of cerebrospinal fluid. “There had been a lot of informative work done in the past, but it was hard to see how the data could be used clinically, because people had been using different collection procedures, reagents, and assays. ADNI has achieved standardization of all things necessary to have reliable biomarkers,” he explained.

ADNI researchers also published results in August reporting the presence of an Alzheimer’s disease biomarker signature of β-amyloid protein 1–42, total tau protein, and phosphorylated tau181P in 90% of Alzheimer’s disease patients, three-quarters of those with mild cognitive impairment, and one-third of normal controls (Arch Neurol 2010;67:949–56). In patients with mild cognitive impairment followed for 5 years, the signature also showed a sensitivity of 100% in patients who progressed to Alzheimer’s. “We now know that Alzheimer’s is probably present in the brain about 10 years before evidence of impairment, and we can see the signal of biomarkers in people who are cognitively normal but have that pathological profile. It makes us think they’ll convert to Alzheimer’s over time,” said Trojanowski.

ADNI also lead to a world-wide network of Alzheimer’s disease-related clinical trials, and in one of the first such arrangements, data from the trial are being posted and regularly updated on a publicly accessible website available to researchers worldwide. ADNI organizers expect the open data policy will speed additional Alzheimer’s-related research.

A Minor Setback

Although right now there’s little physicians can offer patients who have the Alzheimer’s disease biomarker signature, Trojanowski sees only blue skies for the development of treatments. He even is undaunted by the recent failure of a highly anticipated drug trial. In August, Eli Lily & Company halted study of semagacestat after it became evident that the drug not only did not slow progression of the disease, but was associated with worsening cognition. With more than $1 billion invested in at least 100 clinical trials, Trojanowski anticipates that sooner or later there will be a successful candidate therapy. The first drug that shows even modest benefits over symptomatic treatment will shift the focus towards finding treatments that will have a more significant therapeutic effect earlier in the disease process.

All of this has important implications for labs, according to Trojanowski. “The public demand is there, and people will line up for lumbar punctures so they’ll know if they take the drug it will help them. Prepare now for long lines at a lab in your neighborhood,” he joked.

Science as a Team Sport

Treatment or even prevention of Alzheimer’s disease in our time. Successful use of iPS cells in regenerative medicine, drug discovery, and other applications not envisioned today. A new paradigm that harnesses powerful computational and analytic tools to provide completely personalized, wellness-focused medicine. On the surface, these visions, although equally ambitious, complex and compelling, have little in common. However, they share the philosophy that breakthrough science is a team undertaking.

“The same thing that’s been happening in my lab is the same thing that’s happening in science as a whole,” said Thomson. “The problems we are addressing have become so complex that we have to collaborate, we have to reach out to other disciplines, and bring engineering and computational biology together if we want to solve these greater problems.”

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