2015 Director’s Messages

Select a 2015 message from the list below:

Jan. 7, 2015: A New Year, a New Milestone for NCATS and Rare Disease Patients

For people living with a rare disease called a lysosomal storage disorder, a tiny mistake in their DNA leads to big problems on the cellular level. Fatty materials called lipids build up in their cells and tissues, and those deposits can damage the brain, nerves, liver and other organs.

Lysosomal storage disorders primarily affect children, who need daily help from parents and other caregivers to survive. Most of the 50 or so diseases in this group have no treatment, in part because they are so rare. It can take well over a decade and billions of dollars to develop a new drug — a tough commitment for a pharmaceutical company to make for a treatment that ultimately will reach only a few people per year.

A key NCATS focus is finding new ways to understand and develop therapeutics for rare diseases. In an important demonstration of the effectiveness of the NCATS approach, new hope is on the horizon for young people living with the lysosomal storage disorder Niemann-Pick type C1 (NPC). NPC causes lipids to build up, mainly in brain cells, leading to impaired movement, seizures and dementia; patients usually die in their teenage years. Based on the collaborative work of a team including NCATS and other NIH researchers, patient advocacy groups, academic scientists, and a biotechnology company, a promising new treatment for NPC will continue to advance through clinical testing.

The potential treatment is a drug called cyclodextrin, developed by a multi-institutional collaborative team catalyzed by NCATS Therapeutics for Rare and Neglected Diseases program. In collaboration with their partners, NCATS researchers “de-risked” cyclodextrin by developing the drug to the point where private industry — in this case, Vtesse, Inc. — will support further clinical development.

This successful project illustrates several NCATS themes I have touched on in previous Director’s Messages. First, that translation is a team sport: More than 20 researchers from 10 different disciplines and 9 different organizations took part in cyclodextrin’s development:

  • NCATS brought expertise in pre-clinical drug development;
  • Physician-researchers at the Eunice Kennedy Shriver National Institute of Child Health and Human Development brought expertise in NPC biology and clinical care, as did NIH scientists from the Clinical Center, National Human Genome Research Institute, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, and National Institute on Deafness and Other Communication Disorders; and
  • Collaborators from academia and industry, including Washington University in St. Louis, Albert Einstein College of Medicine, the University of Pennsylvania and Janssen Research & Development, LLC, contributed expertise in genetics, biochemistry, animal models and cyclodextrin pharmacology.

The second theme illustrated by the NPC project is the effectiveness of patient involvement in translational research: At every step, multiple patient organizations played essential roles on the team, including funding some of the research. These groups included the Addi and Cassi Fund, Ara Parseghian Medical Research Foundation, Dana’s Angels Research Trust, Hadley Hope Fund, Hide & Seek Foundation for Lysosomal Disease Research, International Niemann-Pick Disease Alliance, John Paul II Medical Research Institute, National Niemann-Pick Disease Foundation, Niemann-Pick Disease Group (UK), and Support of Accelerated Research for Niemann-Pick type C.

The third theme demonstrates NCATS’ commitment to searching for commonalities among diseases, which can help investigators develop therapeutics for more than one disease at a time. NCATS scientists have found that both cyclodextrin and delta-tocopherol — a form of vitamin E — show promise as treatments for NPC as well as other lysosomal storage disorders. The Vtesse collaboration will help NCATS and its partners pursue both of these promising drugs.

With this wonderful news to kick off 2015, I look forward to sharing more exciting NCATS developments throughout the year. Stay tuned!

Christopher P. Austin, M.D.
National Center for Advancing Translational Sciences

Feb. 25, 2015: Rare Diseases Research Illuminates a Path to Precision Medicine

On January 30, I attended a White House event where President Obama announced plans for an ambitious new Precision Medicine Initiative. This exciting effort aims to build on recent successes in developing treatments for certain cancers and other conditions, including rare diseases, based on genetic information. The study of rare disorders has frequently led to new approaches to diagnosis, prevention and treatment that are applicable to more common diseases, and I expect that the Precision Medicine Initiative will be no different.

Balancing excitement about these developments are the daunting challenges that remain for the estimated 25 million Americans and their families living with rare diseases. Although there are several thousand known rare diseases, only about 500 have an approved treatment. These disorders often are severe and difficult to diagnose, creating a substantial unmet medical need and consuming a disproportionate share of health care spending. It can be difficult for biopharmaceutical companies to justify the costs of developing treatments for poorly understood disorders affecting small, geographically dispersed populations, so most rare diseases remain understudied.

NCATS is pursuing innovative approaches to address these obstacles in its Therapeutics for Rare and Neglected Diseases (TRND) and Bridging Interventional Development Gaps (BrIDGs) programs. Drug development experts at TRND and BrIDGs collaborate with outside researchers to advance the development of new therapeutics through scientific and technological innovations that improve drug development efficiency. These efforts “de-risk” therapeutic candidates and thus make them more attractive for adoption by biopharmaceutical companies.

TRND and BrIDGs have achieved remarkable successes in individual diseases, including sickle cell disease and Niemann-Pick disease type C1. But NCATS’ mission to improve the efficiency of the translational process depends on rigorous measurement of aggregate outcomes and comparison with benchmarks. To assess whether TRND and BrIDGs are indeed increasing overall translational efficiency, NCATS teamed up with researchers at the Massachusetts Institute of Technology (MIT), and their analysis was published online in Science Translational Medicine today. The results are impressive, and they validate the NCATS innovation model in unprecedented ways.

The MIT-NCATS team studied productivity data from nearly 30 TRND and BrIDGs rare diseases projects, then compared their success rates, costs and time to completion with published industry averages. The results show that TRND and BrIDGs projects have significantly lower costs and higher success rates, although somewhat longer pre-clinical timelines, than current industry averages. This is extraordinarily exciting because it demonstrates that focusing on scientific and operational innovation can make the translational process much more efficient, giving hope to the millions of rare disease patients waiting for translation to reach them.

This advance is particularly timely in light of the eighth annual Rare Disease Day at NIH on February 27, co-sponsored by NCATS and the NIH Clinical Center. This day-long event is an opportunity for researchers, patients and patient advocates, health care providers, industry representatives, and others to hear about and celebrate progress made in rare diseases research. Planned activities include talks, posters and exhibits, and Clinical Center tours.

As we move closer to the precision medicine vision of individualized data matching patients to therapies, rare diseases research will continue to lead the way, developing innovative evidence-based models for more efficient translation.

Christopher P. Austin, M.D.
National Center for Advancing Translational Sciences

March 13, 2015: The Dose Makes the Poison, and the Genes Make the Difference

Often in today’s world, the word “chemical” conjures up a toxic, man-made substance that is undoubtedly harmful to human health. The growing consumer demand for “natural” foods and cosmetics illustrates this trend. Similarly, the word “drug” can have a different meaning depending on whether it’s considered dangerous (heroin) or helpful (aspirin). In the scientific arena, however, the distinctions between these terms are largely artificial. For example, the widely used stroke and heart attack prevention drug warfarin (trade name Coumadin) has another common use as a rat poison.

Despite the various popular definitions of “chemical” and “drug,” from a biological point of view, they are no different: substances in our environment that can alter how our bodies function in some way, whether beneficial, harmful or both depending on how they’re used and the dose. This commonality is important. From a translational science point of view, we need better methods to assess effects — positive and negative — of chemical substances on human health. I have written about several initiatives NCATS has to develop these methods in previous messages.

Part of the challenge in defining these effects is that individual people can vary greatly in their responses to chemicals. Part of this variation is due to the variation in our genomes. Just as these differences make each of us more or less susceptible to developing conditions such as heart disease, genetic variation also can determine how sensitive we are to the helpful or toxic effects of chemicals. This is the crux of the recently announced Precision Medicine Initiative, which aims to use genetic data from individuals to personalize diagnostic and therapeutic strategies. The same approach might be used to assess individual sensitivity to effects of chemical compounds — but the technical challenges have been daunting.

A multidisciplinary team including NCATS scientists recently demonstrated success in overcoming these roadblocks. In a study published in the Jan. 13, 2015, issue of Environmental Health Perspectives, academic and NIH scientists from the Toxicology in the 21st Century program utilized NCATS’ large-scale robotic screening capabilities to test the cells of more than 1,000 individuals with different genetic backgrounds for sensitivity to 179 different therapeutic and industrial chemical compounds. The study, the largest of its kind to date, not only provided new insights into biological mechanisms of human chemical sensitivity but also revealed that for many compounds, individual responses varied more than previously thought. This new information may help regulatory experts develop more accurate ways to determine safe levels of environmental chemicals.

A better grasp of individual differences in sensitivity improves clinical care and public health, increasing the accuracy of predictions about exposure effects. This improved knowledge helps individuals expose themselves only to chemicals and drugs that are likely to be helpful and to avoid those that are not. That’s the promise of “precision environmental exposure,” much like precision medicine.

Christopher P. Austin, M.D.
National Center for Advancing Translational Sciences

April 30, 2015: A Senator Walks into a High-Throughput Screening Facility…

Last month, I was privileged to play one of my favorite roles — laboratory tour guide — for Maryland Sen. Barbara Mikulski, a longtime and vocal champion of biomedical research. During the tour of NCATS’ laboratories, I used three examples to illustrate our mission of developing translational technologies that will get more treatments to more patients more quickly. NIH Director Francis S. Collins, M.D., Ph.D., joined our walk-through of NCATS’ high-throughput screening facility and helped showcase our multi-armed robot, a machine that can perform tests of potential drugs in one week that would take a scientist 12 years to do manually.

I then showed Mikulski an “organ on a chip” from the Tissue Chip for Drug Screening program, and I explained how these devices are designed to help scientists better understand disease and more accurately and efficiently test experimental therapies. We then held a press conference in the lab, and Collins announced an exciting development for the Discovering New Therapeutic Uses for Existing Molecules (New Therapeutic Uses) program: An experimental cancer drug was found to restore brain function in mouse models of Alzheimer’s disease.

New Therapeutic Uses functions as a “matchmaker,” offering academic investigators an unprecedented opportunity to access investigational pharmaceutical industry assets to explore new ways to treat disease. To speed establishment of these public-private partnerships, NCATS developed template agreements that streamlined the required legal and administrative processes and thus shortened the time in establishing collaborations to about three months from the more typical nine months to one year.

In the Alzheimer’s study, researchers at Yale University found that AstraZeneca’s drug saracatinib, originally intended to treat cancer, reversed learning and memory problems as well as brain abnormalities in mouse models of Alzheimer’s. The team has successfully completed a Phase 1b safety, tolerability and ideal-dosage study in humans and now is starting a Phase 2a clinical trial to test the drug’s effectiveness in older adults with the disease.

We were delighted to share these NCATS accomplishments with the senator during her visit, enabling her to experience firsthand how NCATS is working to transform the long and expensive process of developing new interventions in the quest for improved human health.

Christopher P. Austin, M.D.
National Center for Advancing Translational Sciences

May 28, 2015: Building a Next-Generation CTSA Program

A Japanese proverb says, “None of us is as smart as all of us.” Solving the systemic and highly complex problems of translation will require that adage as a guiding principle.

Bottlenecks in the road to clinical translation threaten this promising future. We know how to sequence billions of DNA base pairs (the “letters” that make up DNA), but we still don’t fully understand what all those data mean biologically or how to manage the resulting volume of information. Solving problems like these requires greater interconnectedness, information sharing and data handling across the scientific community.

NCATS’ Clinical and Translational Science Awards (CTSA) program is designed to address roadblocks that slow the development of much-needed interventions. Just as scientists must innovate to overcome the challenges of translating genome sequencing information into clinical decisions, the CTSA program must evolve to address the challenges and realities of today’s clinical and translational research ecosystem — all with the aim to get more treatments to more patients more quickly.

In continuing its work to evolve the program in this new era, NCATS released the Collaborative Innovation Awards funding opportunity announcements (FOAs) on April 2, 2015. Input from a broad range of stakeholders helped guide the development of this new FOA, which solicits proposals for innovative investigations among three or more CTSA hubs to develop, demonstrate and disseminate multisite experimental approaches that overcome translational barriers in science, operations and training to address high-priority translational science questions.

At NCATS, we are excited to build on the enormous strengths of the CTSA hubs to create a network of unprecedented scope and creativity, suited to the extraordinary challenges — and opportunities — that will turbocharge the translational process to the benefit of science and health.

Christopher P. Austin, M.D.
National Center for Advancing Translational Sciences

June 25, 2015: Innovating in Multisite Clinical Trials

Although a great deal of painstaking work goes into creating and testing potential new treatments before they are administered to people, the most critical and complex stage of the translational process is the testing of interventions in humans for safety and effectiveness. Because these “clinical trials” often require testing in large numbers of people with a particular type of disease, multiple hospitals or other clinical sites usually are needed to study the intervention in a sufficient number of patients in a timely fashion. Similarly, large observational research projects such as cohort studies typically require the collaboration of multiple clinical sites.

Unfortunately, scientific and operational problems currently limit the pace of multisite studies, leading to delays, failures and costs that ultimately slow or prevent treatments from reaching the people who need them. Among other challenges, failures in participant recruitment and delayed trial commencement due to duplicative institutional review board (IRB) reviews and contract negotiations frustrate researchers and patients alike.

NCATS is tackling these system-wide problems head-on in multiple ways, most notably via our Clinical and Translational Science Awards (CTSA) program. Our two recently released funding opportunity announcements — for Recruitment Innovation Centers (RICs) and Trial Innovation Centers (TICs) — aim to transform multisite clinical research for the benefit of patients.

Through the RICs, investigators will develop informatics-driven approaches to assessing the site-specific availability of potential participants during trial planning. These estimates will be based on de-identified, aggregated data derived from electronic health records at individual sites and across the CTSA consortium. Before and during the implementation phase of a clinical trial, the RICs also will collaborate with CTSA investigators to develop innovative strategies for engaging and enrolling research participants in a timely manner.

The TICs will provide innovative infrastructure to establish reliance IRB agreements that allow for the designation of a single “IRB of record” for a given multisite study. An IRB — composed of scientific, nonscientific and community members — must review and approve each new study to ensure that safeguards are in place to protect human participants from harm and that research is conducted ethically. With multisite studies, typically each institution’s IRB would need to approve the study. A single IRB of record removes this need and speeds the trial process. TICs also will offer streamlined contracting to accelerate study start-up.

Working together and across the CTSA hubs, the RICs and TICs will facilitate continuous improvement in research participant recruitment and study conduct across the CTSA network. The RICs and TICs will disseminate these approaches to the larger research community as well.

In conjunction with the collaborative opportunities I discussed last month, these two new funding opportunities will help NCATS continue to evolve the CTSA program to address major roadblocks to efficient translation. The goal is to enable the scientific community to dramatically accelerate the process of translation and, most importantly, get more treatments to more patients more quickly.

Christopher P. Austin, M.D.
National Center for Advancing Translational Sciences

July 22, 2015: Discovering an Old Drug’s New Tricks

I often write about how the inefficiencies so prevalent in the translational process can be turned into opportunities when viewed through the lens of innovation. A striking example is a current statistic in drug development: 80 percent of drugs that enter human testing are never approved for use. One common reason is that clinical studies fail to show effectiveness in treating the disease or condition — the “indication” — the drug was designed to treat. This is frustrating to the patients who might benefit from the new drugs, the doctors who would use them and the pharmaceutical companies that developed them.

But turned on its head, this problem presents a great opportunity to advance translation and health. It turns out that given the connectedness of human biology, a single drug might be effective in treating several different diseases. And the 80 percent statistic means that for every approved new drug, there are four investigational drugs that have undergone years of development and could be rapidly tested in a new indication. Many anecdotal examples of this “repurposing” strategy exist. But the question remains: How do we systematically identify new diseases that these approved and investigational drugs might treat? 

NCATS is taking multiple approaches to solving this problem, two of which reached milestones recently. For the first, scientists used the Center’s high-throughput screening capabilities to test every drug ever approved for human use as well as many investigational medicines — compiled in the NCATS Pharmaceutical Collection — to identify possible new treatments for hepatitis C infection and multiple sclerosis. A collaboration with researchers from NIH’s National Institute of Diabetes and Digestive and Kidney Diseases found that chlorcyclizine, an over-the-counter allergy drug, stopped hepatitis C virus infection in cells and animals, leading to a clinical trial now ongoing at the NIH Clinical Center. And through another collaboration with NIH-funded researchers at Case Western Reserve University, we discovered that a combination of two drugs currently used to treat fungal infections and eczema may hold promise as a treatment for multiple sclerosis.

A second NCATS program focused on repurposing, Discovering New Therapeutic Uses for Existing Molecules, matches NIH-funded researchers with investigational pharmaceutical compounds to identify new indications. This month, NCATS is awarding nearly $3 million to four academic research groups to test whether drugs from pharmaceutical companies AstraZeneca and Sanofi may be effective for treating type 2 diabetes, acute myeloid leukemia (an aggressive blood cancer), glioblastoma (one of the most aggressive brain tumors in adults) and Chagas disease (a neglected tropical disease that causes heart, digestive and neurological problems).

Drug repurposing has enormous potential to get more treatments to more patients more quickly; NCATS’ programs are making this potential a reality.

Christopher P. Austin, M.D.
National Center for Advancing Translational Sciences

Aug. 19, 2015: Starting Off Right: Creating Better Chemical Probes

Creating a new therapeutic is like constructing a building. Both are highly complex, multi-year endeavors that require the contributions of many different disciplines. In each case, a solid foundation is critical: A building constructed on sand and a drug developed on faulty science will both fail.

A crucial part of the foundation for a new drug’s development comes from early tests of the scientific idea, when researchers use prototype drugs — termed “chemical probes” — in model testing systems. If either the chemical probe or the testing system is faulty, the drug’s development program will fail. I have written frequently about new testing systems NCATS is developing to more accurately predict a potential drug’s effects once it has entered the development pipeline, but I have not described our efforts to develop more accurate chemical probes more efficiently.

Chemical probes interacting with their molecular targets have often been referred to in a “key and lock” analogy, with probes being the keys to molecular locks in the body. But the molecular locksmiths — those trying to identify a chemical probe “key” to a particular target “lock” — are at two enormous disadvantages. First, the general principles governing which types of “keys” fit into which types of “locks” are not known, making testing of potential keys trial-and-error. And second, the number of potential chemical “keys” is functionally infinite. The number of potential “drug-like” chemical compounds is 1060 — that’s 10 followed by 60 zeroes — or more than the number of grains of sand on Earth. (For those of you who like nomenclature, that’s a novemdecillion.) Even with the robots at the NCATS Chemical Genomics Center (NCGC), only about 1 million (106) compounds can be tested, leaving the overwhelming majority of chemical space unexplored.

NCATS is taking multiple approaches to this important and exhilarating problem (for those of us brought up on Star Trek, chemical space exploration fires the imagination), and I will discuss these in the future. The end-goal of these efforts is to transform chemical probe (and eventually drug) identification from its current trial-and-error (mostly error) state into a predictive science, wherein a drug for any molecular disease target can be anticipated from informatics-driven computer models alone.

Partially because probe development is so difficult, it has recently become clear that many commonly used chemical probes are actually unreliable experimental tools, leading to faulty foundations for subsequent drug development. The probes’ effects aren’t strong enough, they interact with proteins other than the target, or their biological activity is misleading. Fortunately, several collaborative efforts are underway to address this problem, both within and outside of NCATS. This month, I’m a co-author on a Nature Chemical Biology commentary outlining the promise and issues with many existing chemical probes and offering potential solutions, including a newly developed wiki site called the Chemical Probes Portal. The scientific community can use the portal to disseminate reliable information about small molecules and to crowdsource information about the compounds’ properties and best uses. The goal is for researchers to visit the portal, get answers to their questions, and discover the best probes to use as well as how to use them to generate reliable, reproducible data.

Here at NCATS, the NCGC has developed and disseminated many chemical probes, working with disease-focused collaborators across the globe. The Chemical Probes Portal complements an existing public resource at NCATS, the Assay Guidance Manual, which disseminates information from experts around the world on the best methods to produce and validate chemical probes. 

Through these and related efforts, NCATS is helping to put translational science on a solid foundation. And that will help get more treatments to more patients more quickly.

Christopher P. Austin, M.D.
National Center for Advancing Translational Sciences

Sept. 23, 2015: Powering Precision Medicine

This past January, President Obama announced his intention to launch a Precision Medicine Initiative (PMI) that would enable clinicians to tailor disease prevention and treatment recommendations to each individual based on their particular genetics, environment and lifestyle. Last week, a working group of the NIH Advisory Committee to the Director released a report (PDF - 2MB) that includes a PMI vision for a cohort of more than 1 million Americans participating as active partners in the research process. Although work has just begun to make PMI a reality, a few thoughts from an NCATS perspective immediately come to mind.

PMI has the potential to be a game-changer for translational science by allowing decisions on therapeutic targets, design of clinical trials for new interventions like drugs and medical procedures, and the use of these interventions in wider populations to be more scientifically based. Typical of translational initiatives, PMI will have both scientific and operational challenges requiring innovative solutions. Finally, PMI is designed as a partnership between researchers and the participants who will contribute their data; as I wrote last fall, this kind of patient and community engagement is central to NCATS’ efforts to make translation more efficient and effective.

Beyond the confluence of PMI and NCATS perspectives, the science of precision medicine makes NCATS’ efforts to identify commonalities among diseases and within the translational research process even more timely. A pair of seeming contradictions illustrate this point.

First, a focus on commonalities leads to specificity and vice versa. Increasingly, researchers are recognizing that distinct diseases are really different manifestations of the same underlying cause. For example, the recently initiated NCI-Molecular Analysis for Therapy Choice (NCI-MATCH) Trial will treat patients with drugs specific to their tumors’ genetic mutations, regardless of the organ or system in which the cancer appears. Conversely, scientists are reclassifying many common diseases into smaller and more specific groups, each with a different underlying cause and potential treatment. Grouping people by narrowly defined factors means scientists can tailor interventions to the individuals who can benefit most, but it also means that many common diseases must now be treated like rare diseases. NCATS’ focus on rare diseases research has advanced new methods both to discover commonalities among disorders and to diagnose and test interventions in rarer disorders. These paradigms are tailor-made for the precision medicine era.

Second, although precision medicine studies will include fewer patients, this research actually requires a larger population. Because individuals with specific genetic or other characteristics required for a precision medicine study generally will be widely dispersed, researchers must identify and engage more people with a particular condition to find the few who have the “precise” characteristics. NCATS’ two national clinical networks — the Rare Diseases Clinical Research Network and the Clinical and Translational Science Awards (CTSA) Program — are ideally suited for precision medicine given their scale; access to diverse populations; and ongoing efforts to make participant recruitment, human subjects study review and other translational processes more effective and efficient. For example, the CTSA Program Recruitment and Trial Innovation Centers are designed to transform multisite clinical research by reducing delays in trial start-up and developing innovative participant recruitment strategies.

NCATS looks forward to helping lead the precision medicine charge and thus deliver more treatments to more patients more quickly. Precisely.

Christopher P. Austin, M.D.
National Center for Advancing Translational Sciences

Oct. 27, 2015: Exploring the Translational Science Spectrum

I often write about the NCATS goal to develop, demonstrate and disseminate innovations that speed the translational research process. But what is this “translational science process,” and why is improving it so difficult?

Envision each stage of scientific research, from knowledge about the biological basis of health and disease to delivery of interventions that improve the health of individuals and the public. Traditionally, scientists have thought of these stages as a linear path or “pipeline” moving in one direction:

Basic Research > Pre-Clinical Research > Clinical Research > Clinical Implementation > Public Health

At first glance, this progression makes logical sense. Basic discoveries inform testing in pre-clinical models, and pre-clinical success enables clinical testing. Promising clinical trial results lead to wider adoption of interventions in the clinic, and widespread uptake drives improvements in overall public health. Each step builds on the progress of the previous stage.

Translational science spectrumContrary to this unidirectional, linear conceptualization, the history of medical discovery shows that the translational process can in fact start at any stage and go directly to any other stage, with progress often occuring in multiple directions at once. This multidirectional, nonlinear process is represented by the NCATS “translational science spectrum” diagram. Understanding the dynamics of this system is critical because translational innovation relies on an accurate “mental map” of the process possibilities, as does creating a translational ecosystem that is purpose-built to recognize and capitalize on the many ways translation can occur.

A couple of recent examples help illustrate this nonlinear, multidirectional process. Last month, NCATS researchers and collaborators working in the “Pre-Clinical Research” stage used the Center’s state-of-the-art high-throughput combination drug screening platform to test 13,910 combinations of known and newly identified drugs to treat malaria. Current medications for this deadly infection are remarkably effective, but drug resistance to the treatments is on the rise, creating an urgent need for better therapies. The results were published in the Sept. 25, 2015, issue of Scientific Reports. The entire dataset, including information on 4,600 drug combinations, is available online.

The analyses not only led to the identification of new potential treatments (moving from the Pre-Clinical to Clinical Research stage) but also shed light on the underlying biology of malaria (moving from the Pre-Clinical to Basic Research stage). This bidirectional translational effort produced two simultaneous advances in the fields of malaria research and drug resistance.

In another recent combination drug screening study, NCATS and other NIH researchers combined the approved adult T-cell leukemia (ATL) drug ruxolitinib with more than 450 potential therapeutic agents to observe their combined effects on ATL cell lines. The team identified another agent that works similarly to ruxolitinib; independently, the agents showed modest tumor-fighting effects, but their combined effect was much greater. The treatment extended survival in animal models and blocked growth of cancerous cells from human patients with ATL. Studying the compounds alone and in combination in ATL cells also shed light on the cancer’s molecular pathways. The group published these results in the Oct. 6, 2015, issue of Proceedings of the National Academy of Sciences. Again, these findings provide new knowledge in two directions, enhancing both basic science and clinical research.

NCATS’ focus on not only improving the efficiency of each stage in the translational process, but also creating a translational ecosystem that provides ready pathways among these stages, is key to our strategy for getting more treatments for more patients more quickly.

Christopher P. Austin, M.D.
National Center for Advancing Translational Sciences

Nov. 24, 2015: Making Surprise Family Connections

At this Thanksgiving time of year, we turn our attention to how very different our family members can be despite sharing the same genes. Diseases turn out to be like families this way — a discovery with profound implications for translational science.

Traditionally, doctors and researchers have organized their thinking about diseases around symptoms, or the organs and tissues they affect, rather than underlying biological mechanisms. By contrast, NCATS’ system-wide approach to translation starts with genetic or cellular mechanisms and considers what symptoms or diseases appear in any organ or tissue when those mechanisms break down. When applied to therapeutic development, this approach can lead to rapid advances via sometimes surprising connections, as it turns out that Mother Nature is the original “repurposer.” A given mechanism or pathway is often used to produce a variety of functions in different organs. Thus, a drug with a particular mechanism often can treat multiple different diseases, saving critical time and effort to get more treatments to more patients more quickly.

Recent studies supported by NCATS illustrate the potential of this mechanism-first approach. Several years ago, the pharmaceutical company AstraZeneca developed saracatinib, an investigational drug that blocks the function of a family of proteins called Src kinases, which are involved in cancer formation. (Src is short for “sarcoma,” a kind of cancer.) Clinical trials demonstrated that the compound was safe for cancer patients, but it did not appear to be an effective treatment.

Enter NCATS’ Discovering New Therapeutic Uses for Existing Molecules (New Therapeutic Uses) program, which matches pharmaceutical companies with investigational drugs that have particular mechanisms with academic researchers who have ideas about other diseases that a drug with one of those mechanisms might treat. Although Src kinases were initially identified through their connection to cancer, more recent research shows their involvement in a neurological condition — Alzheimer’s disease — and a rare lung disease called lymphangioleiomyomatosis (LAM).

Two New Therapeutic Uses project teams are testing saracatinib as a treatment for both Alzheimer’s disease and LAM. NCATS-supported scientists at Yale University have shown that the compound reverses brain problems in a mouse model of Alzheimer’s disease and is safe in patients; a large trial of the drug’s effectiveness in Alzheimer’s disease is ongoing now. Additionally, NCATS-supported scientists at Baylor College of Medicine are testing whether blocking Src activity with saracatinib can reduce disease progression in LAM patients. If successful, these projects will have cut many years and millions of dollars off the cost of developing a new drug for these diseases.

This example — the potential of treating three different illnesses on the basis of a molecular characteristic they share — illustrates the importance and power of NCATS’ holistic approach to understanding health and disease and to developing new therapies. So as you sit down to your family’s Thanksgiving dinner with your seemingly disparate relatives, know that diseases also are being reconciled through unexpected biological connections they share, promising a rich translational harvest.

Christopher P. Austin, M.D.
National Center for Advancing Translational Sciences

Dec. 22, 2015: Small Businesses Thrive in Translational Science World

During the holiday season, Small Business Saturday promotes shopping at individually owned businesses to recognize and promote their significant community contributions. It’s always Small Business Day at NCATS, since throughout the year, the Center supports entrepreneurship as an integral part of advancing translational science to get more treatments to more patients more quickly.

NCATS kicked off 2015 with a new small business collaboration: Biotechnology company Vtesse, Inc., of Gaithersburg, Maryland, agreed to support pre-clinical studies led by researchers from the NCATS Division of Pre-Clinical Innovation to develop treatments for lysosomal storage disorders including Niemann-Pick disease type C. Vtesse has exclusively licensed several NCATS patent applications specifically for their use in the treatment of these disorders, and I look forward to sharing updates from this collaboration’s progress.

On an ongoing basis, NCATS’ Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs support the development and commercialization of new translational technologies, including those from minority- and women-owned businesses. A notable success is the plate-washing technology for cleaning high-throughput screening plates, which are usually thrown away after a single use. This process improvement was developed and demonstrated at our Center, then expanded for dissemination to the research community through an SBIR contract award to IonField Systems, in Moorestown, New Jersey. Ten pharmaceutical companies, biotechnology organizations, research universities and other institutes — as well as NCATS — have validated the process’ effectiveness through multiple rounds of testing, and IonField Systems reports having doubled its business in the past year due to these advances made possible with NCATS support. The method already has saved NCATS almost half a million dollars and kept nearly 50,000 plastic plates out of landfills.

Coming up, as the White House announced earlier this year, NCATS’ Clinical and Translational Science Awards (CTSA) Program will play an important role in expanding an existing small business-related effort: I-Corps at NIH, a pilot of the NSF Innovation Corps initiative tailored for biomedical research and designed to help scientists navigate complex business landscapes to bring new health products to market. As part of I-Corps at NIH, NSF’s “train-the-trainer” program will be offered to up to 10 institutions supported through the CTSA Program.

Business partnerships also are vital to the success of NCATS’ Tissue Chip for Drug Screening program: Funded researchers and IQ Consortium members are working together to further test and develop tissue chip devices and discuss marketability and other industry logistics to enable commercial success. Several startups, such as 4Design Bio and Hesperos, have spun out of the Tissue Chip effort, and a number of existing small companies, such as DRAPER and Nortis, have benefited from the program’s progress. In particular, Hesperos and Nortis are developing a fee-for-service business model to support the research community’s need for better ways to predict drug toxicity.

It’s been a great year for small business collaborations at NCATS, and we will continue to work closely and collaboratively with these entrepreneurs to advance translational science for the benefit of patients — in local communities and far beyond.

Happy holidays!

Christopher P. Austin, M.D.
National Center for Advancing Translational Sciences