Understanding the biological process of aging is essential to improving it. Stanford researchers and Faculty Affiliates Professor Helen Blau (who leads the Baxter Laboratory for Stem Cell Biology), and Professor of Mechanical Engineering Juan Santiago (who leads the Stanford Microfluidics Laboratory), as well as PhD candidate John Ramunas, each aim to improve this understanding through their combined expertise.  The story of their ongoing research project, seed funded by the Center on Longevity, exemplifies the organic evolution of research itself and the unexpected value of interdisciplinary collaboration.

THE STORY OF A PROJECT

The story begins with understanding how we heal.  As we age, our healing process deteriorates until it is slow and incomplete in comparison with our younger selves.  This gradual decline is linked to the deterioration of the rest of our system with age, and understanding how to slow – or even halt – its advance could have promising implications for longevity research.

When it comes to the nature of the healing process, there are some key elements that we already know: There are certain molecules crucially involved in healing (though to what extent remains uncertain), and the presence of these molecules diminishes with age.  It is also known that the timing of the molecules’ delivery to an injured area is pivotal to successful recovery.  Thus timing, as well as quantity, can impact the ultimate success of the healing process.

Is it possible that our deteriorating healing process is caused by the diminishing presence of these molecules in our system?  Might there be a way of artificially mimicking the natural delivery of a younger organism, to achieve the same youthful healing process?  These are the questions of aging, healing, and longevity that Blau, Santiago, and Ramunas sought to address: By creating a mechanism that would successfully deliver the crucial molecules to injured and old animals (in this case, the ubiquitous and much-studied lab mouse), the research team sought to pinpoint the biological underpinnings of rejuvenation.

PRACTICAL CHALLENGES

In the natural healing process of a young animal, the molecules involved are delivered at specific times, and in specific quantities.  In order to successfully mimic the natural delivery, the artificial mechanism needed to be similarly exact.  This was the first of a range of challenges:

First, a precise and reliable delivery method necessitated a pump mechanism, propelling the molecules into the system.  Second, the lab mice, being both live and lively, needed to carry the pump with them as they went about their daily lives, requiring the pump to be small and portable.  Third, the mechanism needed to be remotely controlled, as timing was of the essence.

These criteria resulted in the project’s first attempt at a pump, designed to be held in place by a “mouse backpack.”  From this early stage, the project depended on the combined expertise of the three researchers – Blau brought a body of research in the healing responses of mice to injury, Santiago his expertise in mechanical engineering, and Ramunas his interdisciplinary experience which allowed him to support and intertwine both fields.  It was at this point that the team approached the Center on Longevity , which in turn supported the innovative and multidisciplinary effort with seed funding.

Unfortunately, a significant challenge sprang up right away.  It turned out that mice are not only very small creatures, but incredibly agile ones.  Despite a range of designs (including, somewhat incredibly, commercial mouse harnesses), the mice could not be induced to keep their packs in place.

“Mice can squeeze through tiny spaces,” Ramunas described, explaining how the mice quickly and consistently dislodged their packs.  “There was no way to keep the backpacks on them.”

This challenge left one option: implantable pumps.

A FEAT OF ENGINEERING

Suddenly, the project expanded from an endeavor focused specifically on the effect of delivering careful dosages of molecules to one that rested on the development of cutting edge bio-technology.  Given the precision and complexity required for these pumps to function successfully, an entirely new mechanism was needed.  This pump had to be reliable, precise, and very, very small.

“We didn’t want to implant something the size of a backpack,” said Ramunas.  “We needed it to be large enough to function, but not so large that it was cumbersome.”

Making something smaller is dramatically more complicated when that something is a remote-controlled, mouse-implantable micro-pump.  Into the tiny volume must fit: a battery pack, a container for the molecules, a radio control system, and an antenna – all in safe, implantable housing small enough to be mouse-friendly.

Thus began the project’s true challenge: developing a reliable, implantable micro-pump.  A test of innovation and engineering, the team has continued to test, refine, and test again over the past 4 years.

 DEVELOPING THE MICROPUMP

The process of developing the micro-pump is a cyclical process of lab design and live testing.  The lab allows various pump mechanisms and materials to be attempted and fine-tuned, honing the best possible candidate in both size and efficacy.  Live testing is done with a “glowing” solution – mice who successfully receive the substance through the implanted pump literally glow, making observation of the delivery amount and timing plainly obvious.

Once the pump has successfully proven itself, it can be used in a wide range of biomedical applications, not restricted to the study of healing molecules or even aging.  The demands of this project – minute size, remote-controlled function, safely implantable – have ushered in the development of a valuable new technology.

ONE PROJECT, MANY LESSONS

This process of testing, development, and more testing continues today.  Researchers Blau, Santiago, and Ramunas have been joined over the years by a steady stream of enthusiastic students — twenty of which have already contributed to, and been enriched by, this collaborative project.  For Ramunas, it is particularly encouraging to witness this growing interest in research on healthy aging, an area that “is only now becoming mainstream.”

The project has grown significantly in both size and support since its initial seed funding from the Center on Longevity in 2009.  The latest efforts have been supported by a substantial Challenge Grant, and now by a Bio-X grant – both programs well known for their facilitation of innovative interdisciplinary initiatives.  And while the pace of the research’s progression remains unpredictable, this study has already demonstrated that unpredictable transformations are more than an inevitable part of the scientific process — they can prove to be a vital element in a project’s maturation.