Guest Editorial

The NIH Intramural Clinical Research Program: Changing the Trajectory of Care

Steve Holland

Deputy Director for Intramural Research Michael Gottesman recently reviewed the profound effects that the NIH intramural research program (IRP) has wrought over the years on the current conduct of general medicine, including the use of automated blood-cell counting, vaccine development, coronary imaging, protection of the blood supply, and genomic analysis.

Following up, I wanted to highlight a few of the ongoing intramural approaches and trials at the Clinical Center that promise to change understanding and practice in the future. Taking a look at some of our more prominent niches in the landscape of modern medicine may also help us look toward our evolving roles in the future as well.

The treatment of patients with severe illness is special. There is a lot of anguish, a lot of anxiety, and often a lot of death. It takes a special and invested commitment from all involved—patients, nurses, doctors, scientists, administrators, and directors—to sustain the conviction, momentum and support necessary to carry us through the times that are inevitably trying and painful. But if this is where the battle lines are drawn, dare we walk away?

The successes of antiretroviral therapy for human immunodeficiency virus (HIV) started at NIH originally with zidovudine (AZT); was perfected over the years with infection prophylaxis, multidrug combinations, and simplified delivery; and has culminated in a widespread group of drug targets and the cognate drugs that have given us a new paradigm for how serious diseases can be turned. The unconquered frontiers of immune reconstitution and HIV-associated malignancies are slowly yielding through innovative IRP studies.

The eruption of excitement around the dramatic and successful treatments of cancer with chimeric antigen receptors has finally persuaded even the long-standing skeptics that immune control of cancer is real, harnessable, and effective. The deep intramural commitment to the immune control of cancer by Steve Rosenberg’s lab (NCI), which is exploring cell-mediated mechanisms, and Ira Pastan’s lab (NCI), which is using humoral ones, both anticipated and facilitated this development. This effort to focus, train, and release the latent powers of immunity on specific tumors has emerged as one of the most critical and important ways in which we will address cancer in the future.

Development of new tools is essential, of course. But just as critical is learning how to use the tools that already exist. Lou Staudt’s group (NCI) has dissected the molecular signature and definition of lymphomas, enabling their detection and tailoring of treatments. Staudt, Kieron Dunleavy (NCI), Wyndham Wilson (NCI), and colleagues have honed the chemotherapy of lymphoma to a fine edge, using the NIH-established principles of multiagent chemotherapy to achieve terrific cure rates while reducing the need for more toxic therapies.

In the infectious-disease realm: While working to create new drugs for tuberculosis, Clif Barry’s lab (NIAID) has shown how to use the old drug linezolid in the successful treatment of multidrug-resistant tuberculosis. Cindy Dunbar’s group (NHLBI) turned eltrombopag, a drug used for severe thrombocytopenia, into a drug that can rescue a significant number of people who have severe aplastic anemia.

Perhaps our greatest ongoing area of shining success is one that has been a jewel in our diadem for decades: our unique capacity as a community of like-minded investigators to identify specific patient phenotypes; recruit similar patients and their families; bring them in for study; genotype them; understand the underlying mechanisms; and—with hard work and good luck—develop new therapies. For example, the extraordinary work of Marston Linehan’s group (NCI) in dissecting and defining the metabolic basis of kidney cancers has changed diagnosis, screening, therapy, and survival.

The list of new diseases (and the genes associated with them) discovered at NIH stretches way back, but the pace of discovery in the past few years has been breathtaking: novel autoinflammatory diseases (DIRA, NOMID); novel immunodeficiencies (DOCK8, PLCG2, VPS45); novel endocrinopathies (ARMC5, NT5E, EHHADH); novel metabolic syndromes (Proteus); novel cancer syndromes (HIF2A, GATA2); and the remarkable yield of the Undiagnosed Diseases Program led by Bill Gahl. All these new diseases and genes provide even more targets for the massed investigative power of NCATS, promising even more new drugs for the future.

And then there’s the work from Julie Segre’s team (NHGRI), which championed genome sequencing to track a microbe’s spread.

This essay presents a very brief, necessarily inadequate, and incomplete sampler of some of the many things that are ongoing and outstanding in the Clinical Center’s intramural clinical program. What we have changed about the practice of medicine so far is only the prologue.