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NIH Director Francis Collins & 2013 Nobelist James Rothman Kick Off 2015 Annual International Society for Extracellular Vesicles (ISEV) Meeting in Washington, DC

The 2015 annual meeting of the International Society for Extracellular Vesicles (ISEV) (http://www.isevmeeting.org/) got off to a stunning start on Thursday morning (April 23) with back-to-back plenary presentations by 2013 Nobel Laureate James Rothman, Ph.D., from Yale University, and by NIH Director Francis Collins (photo), M.D., Ph.D., addressing an overflow crowd of more than 800 attendees at this, the largest-ever ISEV annual meeting. These two phenomenal speakers and scientists were followed directly by a 30-minute round-table discussion among the two speakers, Dr. Jan Lötvall, President of the ISEV, Dr. Xandra Breakefield of Harvard University, and Dr. Alan Sachs, the CSO at Thermo-Fischer Scientific. Dr. Rothman was the first to speak after brief introductions by Dr. Ken Witwer of Johns Hopkins, chair of the local organizing committee for the meeting, and Dr. Lötvall. Dr. Witwer was quick to thank all the meeting sponsors and especially to highlight the support that had been provided by both the NIH and the NSF, which supported the attendance of over 40 young investigators. Dr. Lötvall briefly summarized the history of the ISEV from an initial meeting in Canada in 2005 that was attended by ~20 people to a 200-person over-subscribed meeting in Paris in 2011, and finally to today in Washinton, DC, where official registration approached 800 and represented 60% growth over that for the meeting held in Sweden in 2012. Dr. Lötvall also highlighted the immense success that has already been achieved by the ISEV’s Journal of Extracellular Vesicles in its brief three years of existence. It is doing “amazingly well,” Dr. Lötvall noted, as journal editors await assignment of an impact factor. After these brief opening remarks, Dr. Rothman then assumed the podium and very quickly demonstrated the kind of clear, incisive thinking that separates Nobelists from the rest of us. The title of his talk was “Principles of Vesicular Transport,” certainly a legitimate subject for him as his 2013 Nobel Prize in Physiology or Medicine was awarded for “discoveries of machinery regulating vesicle traffic, a major transport system in our cells.” That prize was shared with Dr. Randy Scheckman and Dr. Thomas Südhof. The purpose of Dr. Rothman’s address was chiefly to describe the multifarious, long, and difficult efforts that had gone into establishing the nature of vesicle traffic within the cell, in the hope that this might offer insights and/or clues to those now investigating vesicle traffic, particularly that of exosomes, outside the cell. He proceeded to do this eloquently, and also with a clear indication of the extreme scientific rigor that underlay every single experimental effort he undertook.

He did initially make note of the “incredibly rapid advance” of exosome-related studies and acknowledged the possibly major benefits that might proceed from this work, but this came with the implied caveat that the exosome work had to done with the same type of scientific rigor this giant of science had himself always applied so religiously.

Dr. Rothman began his science description by outlining fellow Nobelist George Palade’s seminal description of membrane fusion in 1959, particularly as this would later prove key to vesicle traffic within the cell, and very likely also outside the cell. This work led to the defining of the “secretory pathway,” whereby secreted proteins were systematically moved through the cell—from the rough endoplasmic reticulum to the Golgi body, to vesicles which then fused with the plasma membrane and were exocytosed into the fluid surrounding the cell. Dr. Randy Scheckman developed TS mutants in the secretory pathway and analyzed these to rigorously establish the steps in this critical pathway.

It turned out that proteins can be glycosylated in the Golgi body and glycosylated molecules in the vesicle membrane could serve as targeting molecules, but how did they avoid fusing with other membrane-bound organelles in the cell, when they were intended to move to the plasma membrane was a key question. It was then found that the vesicles were coated (with the COP1 protein coat) that would not permit membrane fusion. But when the vesicle reached the plasma membrane, that coat was then eliminated by a mechanism involving a GTP switch and the vesicle was then able to begin fusion with the plasma membrane. It was then that the investigation of how this membrane fusion took place that led to the identification of the key SNARE complex that is crucial to membrane fusion. It was then determined that the targeting of the vesicle to the membrane with which it is fusing is governed, in a combinatorial way, by the SNAREs.

After detailing this seminal scientific effort, Dr. Rothman took a moment to make some personal reflections. One was that he was so grateful for the grant support he received early in his career and what a science-nurturing environment that created for him. He expressed concern that such benevolent munificent support is not so clearly available today and he worries about the effect that this changed environment may have on the quality and quantity of science.

He closed with a photo of himself blowing bubbles. He said that he had tremendously enjoyed spending 25 years of his career working on bubbles within the cell, and he very much hoped that those in the audience would have just as much enjoyment working on bubbles outside the cell.

Next to the podium was Dr. Francis Collins, now Director of the NIH, and previously head of the National Human Genome Research Institute (NHGRI) and the Human Genome Project.

He began by expressing his delight at being at this ISEV meeting, particularly because he believed that something “really exciting” is going on here and that it has the potential to “turn everything upside down” and that is the kind of science he “truly loves.”

Then, before he got into a specific discussion of exosomes, he outlined some of the current and relevant programs that are now in operation at the NIH. He first put in an impressive plug for the NIH, noting that the Institute has supported 145 Nobel Laureates, including even Dr. Rothman.

He noted that three of the chief focuses at the NIH today are on new technology, new knowledge, and better health; on precision medicine; and on extracellular RNA, particularly as addressed via research funded by the NIH Common Fund.

With regard to new technology, Dr. Collins said that the brain is the current major focus and that is being addressed, in part, by an NIH program called the Brain Initiative. The brain, he said, is a dark place to which we need to bring much more light.
He also highlighted the success of the Cancer Genome Atlas as an NIH-funded effort that is now an enormously useful tool for both researchers and clinicians. He further emphasized the exciting results that have been coming out of the Human Microbiome Project and also the relatively new NIH Roadmap Epigenomics Project.

He then took note of the huge amounts of scientific data that are now being generated and the correspondingly huge need for organizing this data in an efficient and user-friendly way. This is being undertaken in an NIH project titled “Big Data to Knowledge” (BD2K), which will eventually be ramping up to a $100 million/year project, he said.

He then briefly touched on the proposed “Precision Medicine Initiative” and showed a brief video of President Obama mentioning this in his January 20, 2015 State of the Union Address. Dr. Collins observed that everyone in this joint session of Congress stood up and cheered at that announcement, which is not always the case, he said, with topics being discussed in that chamber.

Then he got into his discussion of exosomes and had both very positive comments, as well as some important caveats that researchers need to heed and observe.

He mentioned three subjects in particular. First, how might exosomes be used to send material to nearby cells, or even to far-off cells? Could they represent a “new endocrine-type system, perhaps?”

Secondly, can exosomes be used as biomarkers, giving physicians possibly more powerful insights into cancer and other diseases, allowing both diagnosis and monitoring of disease status?

Thirdly, is there a therapeutic option? Can exosomes be loaded with anti-cancer molecules, for instance, and targeted to cancer cells in a therapeutic approach?

He closed with a caveat, much along the lines of what Dr. Rothman had said, noting that he is worried about the decline in rigor evinced in many scientific papers published today, and he strongly recommends that rigor be restored and revitalized.
He noted this is particularly important in the exciting exosome area, where the multitude of truly exciting possible benefits is electrifying more and more people every day, but the risk is compared with that of early gene therapy work, where sometimes scientists and physicians, in their enthusiasm, got ahead of the sound science, and critical problems and even deaths occurred in patients and brought much of this truly promising work to a virtual halt for some time. This might well have been avoided with rigorous science being done ahead of any premature clinical application.

Finally, although he noted that the day was actually Shakespeare’s birthday, Dr. Collins chose to end with an apropos quote from poet James Russell Lowell.

“Not failure, but low aim is a crime.”

And the clear implication was that aim of all those studying exosomes is very high.

Immediately following Dr. Collins’s address, there was a round-table discussion among Dr. Collins, Dr. Rothman, Dr. Lötvall, Dr. Xandra Breakefield of Harvard, and Dr. Alan Sachs, the CSO of Thermo Fisher Scientific. The discussion was ably moderated by a Matthew Herper of Forbes and much of the discussion revolved around two main themes, namely, the critical need for increased rigor and standardization throughout the exosome research world, and at the same time, the driving forward momentum offered by the awesome potential benefits that these tiny vesicles may have to offer mankind in myriad different ways.

by Mike O'Neill, MA, and Ron Faanes, Ph.D.