Stanford School of Medicine
Department of Otolaryngology-Head & Neck Surgery research teams on Friday, May 34, 2016. ( Norbert von der Groeben / Stanford Health Care )

SICHL is celebrating 5 years of collaborative work towards curing inner ear hearing loss, here at Stanford. As such, we thought that it was a good time to look back at what has been accomplished, discuss where the research is currently and where it is headed in the future.

Below is an in-depth look at the SICHL team’s hard work and hopes for the future of the research, written by Stefan Heller, PhD.

SICHL – the last five years … and … the next five years and beyond

In 2010, I was invited to attend a meeting where Stanford University was trying to define existing challenges in healthcare and how philanthropy might be able to make a difference within a defined time frame. We were split into small groups and each group member was tasked with coming up with a single sentence (less than 25 words) that describes a challenge and offers a solution. Naively, I babbled barely audible, and mainly to myself: “If the University would be able to raise $250 million, we could cure hearing loss in 10 years.” The person sitting to my right, a nicely dressed woman in professional attire (I was wearing T-shirt and shorts) immediately turned her head towards me and responded, “Now, THAT is making me listen to what you have to say.”

She and I had an interesting conversation about my field of research and one of its major goals, namely the search for cures for hearing loss. She was surprised to hear that the field is very small, that probably only 20 laboratories worldwide are truly focused on reversing hearing loss using biological forms of treatments such as novel drugs, gene therapy, or stem cell-based strategies. I explained to her that the inner ear is quite a complex organ, that it is difficult to perform surgeries on the inner ear, that the paucity of cells inside the ear has slowed down molecular and cellular research on how sensory hair cells work, how they develop, and specifically how they can be replaced in damaged ears. She told me about her parents and how they suffer from age-related hearing loss, and we discussed the poor performance of hearing aids and the lack of treatment options – we both agreed that this is a highly frustrating situation.

In the following, I would like to reflect on the last 5 years.  I also want to explain that raising $250 million is not such a simple endeavor, that there is not going to be a one-size-fits-all cure, and that I am very optimistic that cures for hearing loss are within reach in the future. But first things first.

The woman I talked to at this University meeting turned out to be one of the vice presidents of the Medical Development office at Stanford. This office is responsible for all aspects of medical fundraising, which is a very delicate and complex endeavor particularly in the heart of Silicon Valley. The office also coordinates University-wide campaigns, such as raising money for the new hospital, education, for cancer research, autism research, etc. I realized that Stanford’s fundraising campaigns are well organized and well protected; not surprisingly. Sneaking in an “earmark” for a major campaign for hearing loss seemed futile. So, despite the catchy phrase and basic sympathy towards our cause, I felt that raising attention for hearing loss research outside the department would be a difficult endeavor. It was frustrating because I felt that a large donation would truly have the potential to change the world. Of course, I found support for launching a campaign to finding cures for hearing loss among my peers in the department. One of the reasons I came to Stanford, more than a decade ago, was because of a shared vision with our chairman, Dr. Robert Jackler, to build a world class research division within the department that focuses on excellent science and one prevailing goal: to find biological cures for hearing loss. Our research division grew quite a bit from the modest beginnings of just my own laboratory of six people (who moved with me from Boston) now to eight research groups and about 100 people focusing on inner ear biology and hearing loss.

Since the first meeting with the Office of Medical Development, we were wondering about ways to keep the public informed about our research, to keep people engaged, and quite simply to spread the word that support for our work ultimately will make a difference for patients. The “Stanford Initiative to Cure Hearing Loss”, or SICHL, was born to accomplish these goals. Despite the funny sounding acronym, we have not been sickly but highly successful in providing seed funds to high risk projects that would not be fundable with conventional approaches (such as grants from the federal government or foundations). In fact, our seed fund approach is probably the greatest impact a small campaign can have on a group of researchers. Seed fund donations of about 1.5 million dollars to SICHL laboratories have resulted in approximately 15 million dollars in federal grants over the last 5 years. This is a return on investment of 10 dollars for each donated dollar, and shows the impact even the smallest donations can have on funding SICHL research.

Despite these successes, we are far from the original vision: Curing hearing loss in 10 years! It would take a moonshot effort to accomplish this. A major single donation or fundamental nationwide awareness of the issue would be needed to fund such a moonshot campaign. This campaign is still a dream, a vision, an overarching goal. It is hard to raise that much money, but the only way of not achieving our goal is not trying.  And not trying is no option. The good news is that the last year has been the most successful fundraising year for the SICHL initiative, and I feel that even if we are not (yet) taking the moonshot, we are going to experience a major jolt and the search for cures will experience a noticeable acceleration in the next years.

So, how far have we come in the last five years and where are we going in the next five years? A whole generation of trainees – more than five dozen students, postdocs, and visiting scientists – came through our laboratories working on projects that resulted in more than 130 peer reviewed publications (2012-2016), many in leading scientific journals, and all providing advances in science or translational aspects that link basic research with clinical applications. It is impossible to discuss all these advances individually but I would like to highlight some.

First, a collaborative group led by Drs. Tony Ricci and Alan Cheng has identified the mechanism by which ototoxic aminoglycoside antibiotics enter sensory hair cells.  These drugs are very efficient antibacterial agents used to fight life-threatening infections  and do not normally enter sensory cells. Once inside hair cells; however, these drugs create havoc and ultimately kill the cells. The basic scientific finding how aminoglycosides enter hair cells led to a project that investigated modifications of the drug to prevent it from entering sensory hair cells while preserving its antibacterial features. The Ricci and Cheng labs subsequently found a way to change one of the most commonly used aminoglycoside antibiotics so that the drug loses the side effect of causing hearing loss. This major finding is now the basis for a highly focused program to reduce inner ear toxicity of antibiotics without disarming their potential to kill infectious microbes. Replacement of the currently used antibiotics with novel versions that are non-toxic to the inner ear has the potential of preventing millions of new severe hearing loss cases worldwide each year. The goal for the next five years is to get these new antibiotics into the clinic to genuinely make a difference for patients.

John Oghalai’s research group has designed and created an instrument allowing the visualization of the inside of the mouse and human cochlea. The resolution of this novel imaging method, called optical coherence tomography (OCT), is much better than existing methods such as CT scans or MRI. It does not require radiation and it does not require huge magnets; in fact it can be done during or just before surgery.  Five years ago, Dr. Oghalai’s OCT scanner was about the size of a pickup truck.  Version 2 was the size of a large suitcase. The current version of the instrument is the size of a shoebox! We envision that in the next five years, the technology will be tested on human patients when planning inner ear surgeries such as the placement of cochlear implants. Currently, surgeons have very little information about the specific anatomical shape of a patient’s cochlea; existing scans do not deliver high enough resolution. As a result, cochlear implants are placed in a generic fashion, without taking into consideration a patient’s specific anatomy. OCT has the potential to revolutionize this process, allowing the surgeon to precisely guide a cochlear implant to the best possible position inside the cochlea; thereby generating a better coupling of the cochlear implant with the nervous system, which in turn will result in better working cochlear prostheses. Precision Medicine is a current buzzword describing personalized approaches to modern medicine and Dr. Oghalai’s OCT scanner is at the forefront of this movement.

Finally, the Heller laboratory has been pioneering work on isolating and manipulating a special kind of inner ear cell outside of animals. These so-called otic progenitor cells can be generated from a rare group of stem cells that reside in the mouse and human inner ear. The progenitors can conveniently also be generated from embryonic stem cells. Focus in the last years was on generating otic progenitor cells more efficiently and on finding ways to purify the cells. Right now, the otic progenitors cannot be obtained pure enough for conducting serious efforts towards drug screening or even cell transplantation. The latter results in tumors, which is not a desirable outcome. This long-standing research project will enter a new phase in the coming years in which stem cell-generated inner ear cells will potentially be used for the first time in efficient screens for new regenerative drugs. Whereas, the issue of purifying the cells is potentially going to be solved in the upcoming years, it is still a desirable goal to further increase efficacy. Although the search for novel drugs is not a trivial endeavor, we are optimistic that first candidates will emerge in future years; how many years? Difficult to tell. Luckily for patients this is not a SICHL exclusive goal.  Beside the few research laboratories worldwide focused on finding possible drugs candidates, there are now more than thirty biotech companies some backed up by large pharmaceutical companies who believe that cures for some forms of hearing loss can be found and brought to the market.  This is an exciting time, and SICHL supported research will without a doubt play a role in the discovery of novel drugs in future years.

These three projects are just examples for the many research projects in SICHL.  Some projects previously were highlighted on this blog but many fundamentally important projects were perhaps not “sexy” enough to be featured. Nevertheless, each project advances our knowledge – even the negative results are worth reporting because making others aware of roadblocks and dead ends ultimately makes the whole effort more efficient.

Finally, a few more comments about how we conduct our research and how research covered by the SICHL initiative will change the world in future years. The published work of our group is regarded as highly credible and fundamentally solid, but also highly creative, pushing boundaries and advancing science by finding answers to important and crucial questions. We can be proud of setting a high standard that focuses on the basic scientific process. Going the extra mile might appear uneconomical at first, but in the long run it is important to build a credible trajectory that does not promise pie-in-the-sky accomplishments without first establishing a solid scientific basis. We are all very happy to be part of a select group of scientists who can collaborate on one common goal and that is to eliminate hearing loss. We are thankful for the support SICHL donors have provided in the past and we are highly optimistic that the best years of the most exciting discoveries and advances are yet to come. Building on the fundraising success SICHL had in 2016, I am hopeful we will get closer to the goal that remains:the moonshot to cure hearing loss.