Basic Science: The 98% We Still Don’t Know

There is a growing sense not only in academia but also in industry that in many therapeutic areas we simply don't know enough about the basic biology of disease to effectively pursue treatments for them. Drug development in areas such as HIV/AIDS and Alzheimer's have been brought up short by a sense that we may be shooting in the dark at unclear targets – that we're wasting ammunition, so to speak. At a Partnering for Cures panel, we took a step back to look at the fundamental building blocks of our R&D enterprise to see what questions remain unanswered and why.

Moderator Cecilia Arradaza of FasterCures opened the discussion by noting that too many breakthroughs go far enough along in the development process but don’t see the light of day. Turning to panelists representing key sectors of the medical research enterprise, she focused the discussion on identifying tools, technologies, or approaches that will allow us to get to some of these vital answers.

“We know much less than we really need to know about almost every single disease, from rare diseases to very common diseases, because we don’t know enough about what causes diseases and also about heterogeneity of expression,” explained William Chin of Harvard Medical School. Chin reinforced the need for a systems approach to understanding disease. Thomas Insel of the National Institute of Mental Health agreed, and pointed out that “there are lots of reasons why studies fail… there is often unpublished data that could lead others to know that what they are doing is a dead end.” Insel said that forums such as http://clinicaltrials.gov were ways of disseminating valuable information, but that competition may inhibit some scientists from publishing critical data.

Matthias von Herrath of the Type 1 Diabetes Research and Development Center at Novo Nordisk elaborated on the issue: “It is important to work together and break down silos and sequestered areas. Where we fall short is in understanding negative data. This is a fundamental problem in both academia and industry.” Von Herrath further emphasized the value of sharing failures and realizing that difficulties arise when there are only incentives for successes.

Brian Mansfield of the Foundation Fighting Blindness described his perspective on animal models, which are a critical link in the translation of basic science to clinical practice, but are not predictive for all diseases. He cited the example of mouse models, which are easy to breed and cost-effective, but can be very different from humans. Mansfield also said “there are lots of constraints on gene therapy.” For example, many people think they can get gene therapy once the gene that is causing their illness has been identified, but that is not always the case.

Panelists agreed that an overwhelming list of questions remains unanswered. Insel noted that we may only actually know about 2 percent of what we should – an optimistic view, according to other panelists. To improve upon this, facilitating a culture change was necessary, they said. Mansfield argued that the basic science culture needs to be changed in a way that would definitively help patients, and suggested that grant-awarding organizations should make it mandatory to publish both positive and negative data as a condition of accepting the grant. Both Insel and Chin agreed that creating teams of individuals with several different perspectives would help advancement in the field. Insel added that collaboration is key, but ultimately, most discoveries are driven because of one individual investigator taking the lead. Von Herrath pushed for the necessity of “tangible incentives” and a cooperative culture that can accelerate translation of basic knowledge into effective therapies.

In all, the panel noted the importance of striking the balance of investing in basic science that allows us to understand the biology of disease while also creating an environment that allows serendipitous paths that lead to new therapeutics.

NCATS: Improving Outcomes from the Same Inputs

Last week, over 1,000 participants from all sectors of medical research participated in a virtual town hall with the interim leadership of the new National Center for Advancing Translational Science (NCATS) at NIH to discuss the status of the effort. NCATS is the first new Center at NIH in a dozen years.

Convened by FasterCures as part of its Webinar series, it was a follow-up to a previous FasterCures web event held in March 2011 in which NIH director Francis Collins had laid out the vision for this new Center.

Dr. Tom Insel, acting director of NCATS (and director of the National Institute for Mental Health at NIH) laid out the Center’s mission, which in brief is “to pursue opportunities for disruptive innovation” in the process of translating promising discoveries into new diagnostics and therapeutics, and to “study the pathway and reengineer the pipeline” in ways that will benefit all players in the system. NCATS, he said, “is disease agnostic. We’re looking at generic innovations across many different diseases.”

Insel was careful to emphasize that the purpose of NCATS is to “facilitate — not duplicate — other translational research activities supported by NIH; to complement — not compete with — the private sector; and to reinforce — not reduce — NIH’s commitment to basic research.” He said that “most of the pieces of NCATS existed before [within NIH]. We’re trying to improve the outcomes from the same inputs.”
Insel summarized some of the innovative programs that are now housed within or are being contemplated for NCATS, such as :

• The NCATS Pharmaceutical Collection (NPC), a comprehensive resource of 3,800 approved and investigational medicines to facilitate repurposing of medicines;
• Research Electronic Data Capture (REDCap), a Secure Web application that enables investigators to: create standardized surveys, easily transfer data, and export data into a variety of statistical programs;
• The Learning Collaborative, a cross-sector collaboration to repurpose an approved drug for use in leukemia (which will be the topic of a FasterCures Webinar on March 21st);
• An NIH‒FDA‒DARPA collaboration that aims to develop a tissue chip that mimics human physiology to screen for safe, effective drugs; and
• An NIH–industry “compound rescuing initiative,” which would match compounds from pharma’s “virtual medicine cabinet” with NIH-funded scientists’ innovative ideas for new uses.

Margaret Anderson, FasterCures executive director who moderated the web meeting said that NIH’s efforts to establish NCATS is an efficient and effective way to thread the needle of existing work and make headway on de-risking the medical research process.

Dr. Chris Austin, Director of NCATS’s Division of Pre-Clinical Innovation and Dr. Kathy Hudson, NCATS Acting Deputy Director both answered questions from participants about collaboration with other stakeholders. Austin said he sees NCATS “as a collaborative instrument,” and that they are seeking the best ideas and best opportunities from outside researchers and funders. Hudson said “partnerships are an essential ingredient for NCATS,” and that input would be sought via a number of advisory groups, in addition to working with industry and other partners on specific projects.

Dr. Josephine Briggs, Acting Director of NCATS’s Division of Clinical Innovation, answered questions about the future of the Clinical and Translational Science Awards (CTSA) program, a network of 60 academic institutions which is the largest single component of NCATS, representing about 78% of its budget. She said that “the CTSA consortium is absolutely essential in the implementation of best practices” developed through NCATS, and that going forward NIH would be “focused on making sure the CTSAs are truly a networked consortium.”

Insel also noted that “unique and in some cases unprecedented scientific opportunities that exist drove the creation of NCATS.” He emphasized that this new center is a catalyst for medical progress, leveraging larger investments at the 26 other institutes and centers at NIH to make sure they have a greater impact. In the long term, he said, success will be measured on whether NCATS can catalyze clinical research to be “cheaper, faster, and better.”

Patients are waiting.

View archive of the Virtual Town Hall with NCATS leadership.