Why rogue? Rogues break rules when the old rules no longer work. That is what is happening in the world of Precision Medicine.

A parade of individuals — some researchers in university labs, some engineers, some parents of loved ones afflicted with rare diseases — told their stories of rule breaking, barrier busting, and cage rattling at the Precision Medicine 2016: Rogue Therapeutics conference held June 22 at the Joseph B. Martin Conference Center at Harvard Medical School (HMS). Their work is challenging the prevailing model of medicine, traditionally rife with anecdote and outdated conventional wisdom, to a practice that is becoming — slowly, but necessarily, according to many speakers — an information-rich, precisely driven process.

These individuals are also rogues because the tools and measurements they require have yet to broadly enter the mainstream of clinical practice. For example genetic testing is precision information that has recently entered medical practice with much fanfare. For better or worse, rather than expert clinicians, it was Angelina Jolie’s viral ‘op-ed’ about her decision to take action in response to her high genetic risk of breast cancer that has moved public awareness and use of these tests. Still, said panelist and longtime-science journalist Carey Goldberg, “It’s not on the public’s radar.”

It may not even be on most physicians’ radar, according to a recent report from STAT.

And that is exactly why these rogue activities are so important. The potential for well-informed medicine exists or is within reach. The problem, said Zak Kohane, conference organizer and Chair of the Department of Biomedical Informatics (DBMI) at HMS, is complacence. “By not being impatient, by saying, ‘This is the pace that medicine goes at,’ we allow millions of people to suffer all the time.”

Rare Disease Informants

When Karen Aiach learned in 2005 that her six-month old daughter Ornella had a rare inherited lysosomal storage disease called Sanfilippo syndrome type A, she was stunned. In this rare disease, a gene mutation knocks out an enzyme that clears toxins from the brain. As the toxins build up, children with the disease become hyperactive and sleepless, they lose cognitive functions like language, and they typically do not live through their teens.

There was no treatment, and doctors told Aiach to go home and enjoy the time she had remaining with her daughter. She did, but she also left her career in financial services and set out to develop a drug for the disease. She put together a team, and just six years later had developed gene therapy to restore the missing enzyme. She chose this bold therapy even though several years earlier, a patient had died from unrelated gene therapy. “In this dire situation, taking an aggressive approach made sense,” said Aiach.

Ornella received the therapy at age six. Now eleven, she sleeps at night, is calm rather than destructively hyper, and while she has not regained the language skills she’d already lost, she does not appear to be losing more skills.

Aiach’s company Lysogene is now working to bring the therapy into Phase 3 trials in 2017 with the aim to gain US regulatory approval. The company has also begun development of a similar gene therapy for another related disease. The progress is impressive.

But, asked Kohane, “what business model will work?”

Aiach is banking on high prices and an expanded portfolio, a scheme that depends on reimbursement, a problem that is yet to be solved.

The value, however, may go beyond profitability. “I believe rare diseases unlock the potential for innovative therapies,” Aiach said.

Based on similar thinking, the National Institutes of Health launched a local program in 2008, the success of which led to formation of the nationwide Undiagnosed Diseases Network (UDN) in 2012, to help the thousands of Americans suffering without diagnoses. Patients send medical records and, if accepted, spend up to a week as in-patients, where a team of experts performs diagnostics. The system, for which DBMI provides data and clinical protocol coordination, analyzes genetic sequencing and other clinical research data for individual patients and has already identified over 100 potential new diseases.

The goal is to begin to systematically confirm and understand these new diseases by finding additional cases and, ultimately, work up new therapies that may have a wide reach. “If we find a target with a mechanism that is druggable, it could apply to other diseases,” said William Gahl, Clinical Director of the National Human Genome Research Institute and a founder of the program on which the UDN was modeled.

This research into rare diseases is also expanding the notion of Precision Medicine. “It’s not just genomics,” said Gahl. “It’s experts getting all the information and working together to determine the best way to proceed.”

Unconventional Therapeutics

While Precision Medicine may bring to mind targeted drugs that aim to hit a molecular target, new devices and techniques are expanding the ways in which precision information about individual patients is being used to manage disease.

One such therapeutic is a high-tech insulin-dosing device for managing Type 1 diabetes, a disease that requires injected insulin for survival. Existing insulin pumps require constant glucose monitoring and delicate adjustments to insulin levels. Too much or too little can be life-threatening. Edward Damiano, professor of biomedical engineering at Boston University and father of a boy with the disease, decided to try to do better. “It’s an engineer’s dream, a dynamical control process,” he said.

Damiano was not part of a medical device company, so he leveraged all of the resources around him to turn his idea for a bionic pancreas into reality. The device allows diabetics to live without diet and exercise restrictions by adapting to their individual needs in real-time. It is poised to begin clinical trials in 2017. “It’s the epitome of personalized medicine in your pocket,” said Damiano.

Devices have a clear path forward, since the US Food and Drug Administration regulates them, but surgical techniques do not. In 1954, surgeons made a bold move. They operated for the first time on children with fatal congenital heart defects. “Maverick surgeons tried out of the box ideas on patients and saved their lives,” said Alison Marsden, professor of pediatrics and computational and mathematical engineering at Stanford University.

The procedures used then have not changed much since, but now researchers know a lot more about the heart, and they have tools, such as computer simulators, that could be used to improve surgery. These simulators, akin to those used to design a new airplane, can be used to model a patient’s specific heart defect and compare alternate, individualized repairs. The next step is to perform the surgery on humans. “A leap of faith is still required on the part of the maverick surgeon,” says Marsden. “Someone has to try it.”

Rogues, Meet the Regulars

These bold and impatient individuals are working at the forefront of Precision Medicine and, as a result, are finding the barriers to progress, such as tenuous business models, unclear approval paths for novel therapeutics, and the challenges of implementing interdisciplinary collaboration.

A panel speaking about medical marijuana illustrated the bind that can occur when novel medicine ducks around barriers rather than working through them. While cannabis is a legal drug in many states, it is not regulated by the FDA. It is medicine by way of a legal end-around. This has become problematic because researchers cannot study the various forms of the drug that patients are using. “We have a lack of standards and a lack of knowledge about basics like dosing and storage,” said Ryan Vandrey, associate professor of pharmacology at Johns Hopkins University. “There are barriers to the research, but it needs to get done.”

These stories suggest that Precision Medicine is only beginning to shape itself. The sources of information it draws on for precision are growing, as are the ways people are finding to bring information, people and patients together to implement it. The value Precision Medicine brings to patients in the future will depend on how well the rogues and the regular players co-navigate the barriers that are cropping up right now. “We get into trouble by ignoring these issues and plowing ahead without realizing there will be stumbling blocks,” said Kohane.

Other speakers included Ashish Jha, Harvard T.H. Chan School of Public Health, Gail Marcus, MCPHS University, and Joseph Newhouse, HMS, on a panel about the drivers of Precision Medicine; Matt Might, University of Utah, Eric Minikel and Sonia Vallabh, Broad Institute, and Alison Skrinar, UltraGenyx Pharmaceutical, on a panel about patients as their own medical advocates; Donald Abrams, University of California San Francisco, Kari Franson, University of Colorado School of Pharmacy, and Larry Wolk, Colorado Department of Public Health and Environment, on a panel about marijuana; Daniel Anderson, MIT, and George Church, HMS, on a panel about engineering disrupting therapeutics; and David deBronkart, e-Patient Dave, with closing remarks about patient empowerment.