Letter from the Biologist - Inke Nathke

As one of the few biologists involved in SONOPILL, I used to feel a little like a Martian amongst the others.  However, this was by no means an unpleasant experience and I never felt unwelcome or unvalued.  In fact, it means I have learned and continue to learn a lot.  It provided the opportunity to tell others about the things I am interested in and share my enthusiasm for cells and tissues.  Another positive outcome is that I am not just learning about the engineering and physics aspects of ultrasound and associated technology, but also about how approaches and attitudes to science differ between biologists and physicists/engineers.  Altogether, this has made me feel less otherworldly within the SONOPILL team and I increasingly enjoy being part of it.

An important discovery I made is that for a physicist/engineer, developing a method to make a specific type of measurement seems to be the fun bit.  Once accomplished, the best and most important part of the journey is over and collecting data using the method is a means to validate the method, but overall that is pretty boring.   I can see why that would be.  However, for the biologist, this is the point where things start and get exciting because it allows lots and lots of data to be collected.  This difference can create challenges when trying to reap the fruits of SONOPILL.  For instance, we need to scan yards and yards of intestinal and colonic tissue to compare what ‘listening’ and ‘looking’ reveal so that we can learn about early changes in cancer that are not detectable by conventional means.  In my lab we spend immensely long times to obtain quantitative data about tissue architecture using optical methods.  That makes access to a technique that involves a simple scan and can produce numbers to describe tissue architecture, a dream come true.  The idea that the numerical parameters generated from acoustic data can reveal the ‘regularity’ of a tissue, show how much cell death there may be, how large cells and/or nuclei are, how regularly they are arranged, how straight the test tube-like tissue invaginations, called intestinal crypts, are in a large section of dissected gut tissue or in situ, is immensely exciting.  Not just because it would make our lives in the lab ever so much easier, but also because it means we could make such measurements in patients.   The ability to detect tissue abnormalities non-invasively and independently of the visual acuity of the human eye or the ability of the endoscope to point to ALL directions as it moves along the tissue is an enormous step forward.

I am interested in how the molecular and cellular changes produced by common tumour-associated mutations translate into tissue, changes at early stage of cancer.  A tool that can measure the consequences of such mutations for whole tissue, provides a realistic translation from our lab-bench experiments to the bedside.  However, to understand how acoustic and optical observations are related, requires lots and lots of data.  That means the data we have gathered so far is just the beginning.  This data is described in a manuscript that is currently awaiting a decision about where it will be published.  It shows the direct comparison between high-resolution optical data and microultrasound measurements of small intestine in mice that are healthy or at various stages of developing small polyps (an early stage of cancer).  Our data show that the less regular organisation of precancerous tissue we measured in three dimensional tissue samples using optical imaging, correlated with elevated and more variable backscatter and acoustic impedance of the microultrasound signal.  This is the beginning of a new direction for my research.  It raises many more questions than it answers.  For instance, what in the tissue is the major contributor to scattering?  Nuclei, cells, crypts, all of them?  Can we dissect the individual contributions of these components?  What does the ultrasound data reveal about their mechanical properties?  This in turn raises questions about how the (mechanical) properties of cells produce the mechanical properties of the tissue structures they form.  Does the acoustic impedance report on the epithelial layer or the mesenchymal tissue including the contractile myofibroblasts below it?  How can we find out?  Knowing the answers to these questions will require many measurements of lots of different samples.  It also means that we need standardised, calibrated methods for measuring and calculating backscatter and acoustic impedance so that values obtained using different ultrasound scanning systems can be compared directly.  All of this requires biologists, physicists, engineers, mathematicians, physicians, and other health workers to communicate and work together, to speak and listen to each other.  SONOPILL has provided a highly effective environment where this is possible.