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IN MEMORIAM
Dr. Frederick Sachs
(1941-2023)
A Beacon of Inspiration, Creativity, and Innovation in the Mechanobiology World
Dr. Frederick “Fred” Sachs, said that my thesis project in the lab was to use a tiny fishing rod – atomic force cantilever – to attach to a single voltage sensor of an ion channel that resided on a membrane of a whole-cell voltage-clamped cell and to directly measure the movement of this voltage sensor, thereby putting to rest the biggest question at the time – how much does an ion channel voltage-sensor move? The beauty of this experiment instantly grabbed me, and while we got only halfway there, our work moved multiple fields, both in biology and engineering[1]. This was classic Fred. “Fred thought he could do anything,” Fred’s longtime friend and colleague, Dr. Tony Auerbach said, and to do things that were not thought possible, “he invented a lot of stuff,” said colleague Dr. Phil Specht. Fred, while “he would push you to the limits,” he also “stuck his neck out,” when it came to doing the very difficult said Dr. Falguni Guharay. These thoughts are consistent with the “Sachs principles” that Fred’s classmate and pal, Dr. Richard Feinman summarized as: First, “It’s so hard to do anything, you may as well do something important,” second, “There is nothing in biology that isn’t connected in feedback,” and third, “As long as there is direct deposit there is no reason to retire.”
With heavy hearts and profound gratitude, we honor Fred, a luminary in the field of cell and membrane biophysics and mechanosensitive ion channels, whose sparkling insight, intelligence, warmth, mentorship, and groundbreaking research have left an indelible mark on the hearts and minds of all who knew him. Dr. Sachs's passing on December 27th, 2023, at the age of 82, brings a profound sense of loss to our community, tempered only by the rich legacy of discovery and compassion he leaves behind. Dr. Sachs was faculty at the State University of New York at Buffalo (SUNY Buffalo) for nearly 50 years where he reached the highest faculty rank of SUNY Distinguished Professor. His contributions reached far and wide through an incredibly perceptive feel for the physics of biology and for inspiring several generations of trainees and colleagues.
From the earliest days of his career, Fred was propelled by boundless curiosity, a keen observational eye, and a deep belief in the power of physical sciences in unraveling the mysteries of life. Fred’s training was with visionary scientists Drs. Alex Bortoff and Harold Lecar, who with Fred’s assistance pioneered electrophysiology approaches[2] and theoretical biophysics[3] that were grounded in physical biology. In the early 1980s, shortly after the clamp technique was born, Fred was working with his post-doctoral fellows, Drs. Tony Auerbach and Falguni Guharay on acetylcholine receptors. Yet, what caught Fred’s eye was activity that looked like ion channels that happened during seal formation by suctioning on the back of the patch pipette. Many thought this was noise or patch breakdown. But Fred’s physical intuition suggested that these were mechanically gated non-selective cation channels (at the time called stretch-activated channels, or SACs) and that most cells had them. He pursued this hunch for the rest of his career, starting with the seminal publication in 1984 showing that non-specialized cells have single mechanically gated ion channels[4]. Working closely with his long-term colleagues, Drs. Tom Suchyna and Philip Gottlieb, and many others who came through the vibrant lab, Fred elucidated channel biophysics of the mechano-gated ion channels[5, 6] and discovered GsMTx4, a tarantula toxin, its structure, binding, and block mechanisms[7], and these matched the Piezo channels that Dr. Ardem Patapoutian discovered in 2010[8]. These systematic and innovative efforts put Fred at the vanguard of biophysics, helping to pioneer this field of mechanosensitive ion channels and inventing and polishing the tools to study them, with his contributions recognized by the Kenneth S. Cole Award from the Biophysical Society in 2013, and having the field he helped build found and build culminate with a Nobel Prize in 2021 to Dr. Patapoutian[9]. Fred’s work was always characterized by doing hard things and having diversity and depth, ranging from the exploration of mechanically gated ion channels to the intricacies of cellular and tissue physiology.
In his work, Fred recognized the need for tools to study these channels, and how the mechano-biology that surrounds them affects their function. So, he built many of the tools we now use in this field. Fred's contributions were not just milestones in the scientific community but paradigm-building and -changing discoveries that served as beacons that guided the path forward. Fred’s genius lay not only in his biological and biophysical insights but also in the tools and methodologies he developed. His innovations are testaments to his ingenuity and his commitment to advancing our understanding of the natural world. The wide-ranging tools Fred developed included QUB software with Drs. Tony Auerbach, Lorin Milescu and Feng Qin[10], and the high-speed pressure clamp with Dr. Stephen Besch[11] to study single mechanically gated ion channels, and the work we did with Dr. Ken Snyder on atomic force microscopy (AFM) cantilevers[12-14] or genetically encoded force sensors with Dr. Fanjie Meng that convert force into light[15] were conceptually mind-bending at their inception, with time became entrenched as gold-standard tools and have illuminated physical phenomena. These tools, along with his studies on ion channels and cellular mechanics, have illuminated the complexities of diseases affecting millions, from anemia[6] muscular dystrophy, to Alzheimer disease[16].
Yet, to speak of Dr. Sachs's achievements without mentioning his extraordinary human qualities would be to paint an incomplete picture. Fred possessed a warmth that knew no bounds. His “Hi, bubs!” in the late mornings when he strode into the lab to the vibrant discussions around ever-brewing coffee that Bev Harlos tended to throughout the day, warmed hearts and energized our thoughts. Fred’s lifelong love for music, especially banjo-playing folk and bluegrass, brought his people together and frequently kept them close for life. Fred was a mentor in the truest sense of the word, guiding, inspiring, and empowering a generation of people and scientists with his wisdom, humility, and endless encouragement. His scientific children have reached far and wide with their studies in the world of mechanobiology and beyond, and his legacy is not only etched in the annals of scientific discovery but in the lives of those he lifted.
We will no longer get to directly experience Fred’s passion for understanding the world, answering difficult questions, and his humor. But our memories of Fred and his inspiration of so many are immortalized by his younger brother Jon Sachs, who put together a collection of reflections by his friends, classmates, and colleagues , a typical Fred lecture, and more tales about Fred (https://www.speaking-of-fred-sachs.org/colleagues-on-fred/). Fred's spirit will forever inspire us to reach beyond our grasp, to nurture the potential in others, and to approach our work and our lives with wonder, compassion, and love.
Fred lived a life – full of curiosity and a fearless pursuit to understand science and life, dispensing his unique thoughts and feelings to those who loved and respected him, living, loving, and mourning fully, like he did when his son Chris passed unexpectedly. He shared his remarkable ability to connect with people, to share in their joys and challenges, and to make each individual feel seen and valued. His laughter was contagious, his counsel sought after, and his company cherished by all who had the privilege of knowing him. Fred's passion for science was matched only by his love for his family, friends, and students, whom he regarded as his extended family. As we bid farewell to Dr. Frederick Sachs, we are reminded of the incredible impact one individual can have on so many lives. Fred's journey was one of profound discovery and human connection. As we forge ahead, inspired by Fred's trailblazing spirit, may the force of curiosity and zeal for life guide us to new discoveries and deeper connections.
Select Dr. Sachs References
1. Beyder, A. and F. Sachs, Electromechanical coupling in the membranes of Shaker-transfected HEK cells. Proceedings of the National Academy of Sciences of the United States of America, 2009. 106(16): p. 6626-31.
2. Bortoff, A. and F. Sachs, Electrotonic spread of slow waves in circular muscle of small intestine. Am J Physiol, 1970. 218(2): p. 576-81.
3. Sachs, F. and H. Lecar, Acetylcholine-induced current fluctuations in tissue-cultured muscle cells under voltage clamp. Biophys J, 1977. 17(2): p. 129-43.
4. Guharay, F. and F. Sachs, Stretch-activated single ion channel currents in tissue-cultured embryonic chick skeletal muscle. J Physiol, 1984. 352: p. 685-701.
5. Bae, C., F. Sachs, and P.A. Gottlieb, The Mechanosensitive Ion Channel Piezo1 Is Inhibited by the Peptide GsMTx4. Biochemistry (Mosc), 2011. 50(29): p. 6295-300.
6. Gottlieb, P.A. and F. Sachs, Piezo1: properties of a cation selective mechanical channel. Channels, 2012. 6(4): p. 214-9.
7. Suchyna, T.M., et al., Bilayer-dependent inhibition of mechanosensitive channels by neuroactive peptide enantiomers. Nature, 2004. 430(6996): p. 235-240.
8. Coste, B., et al., Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science, 2010. 330(6000): p. 55-60.
9. Martinac, B., 2021 Nobel Prize for mechanosensory transduction. Biophys Rev, 2022. 14(1): p. 15-20.
10. Qin, F., A. Auerbach, and F. Sachs, Estimating single-channel kinetic parameters from idealized patch-clamp data containing missed events. Biophys J, 1996. 70(1): p. 264-80.
11. Besch, S.R., T. Suchyna, and F. Sachs, High-speed pressure clamp. Pflugers Arch., 2002. 445(1): p. 161-166.
12. Beyder, A., Electro-mechanical measurements on membranes of Shaker-transfected cells., in Physiology and Biophysics. 2005, University at Buffalo, State University of New York: Buffalo. p. 1-179.
13. Beyder, A., C. Spagnoli, and F. Sachs, Reducing probe dependent drift in AFM with symmetrically supported torsion levers. Review of Scientific Instruments, 2006. 77: p. 056105.
14. Beyder, A. and F. Sachs, Microfabricated torsion cantilevers optimized for low force and high frequency operation in fluids. Ultramicroscopy, 2006. 106: p. 838-846.
15. Meng, F., T.M. Suchyna, and F. Sachs, A fluorescence energy transfer-based mechanical stress sensor for specific proteins in situ. Febs J, 2008. 275(12): p. 3072-87.
16. Maneshi, M.M., et al., Enantiomeric Abeta peptides inhibit the fluid shear stress response of PIEZO1. Sci Rep, 2018. 8(1): p. 14267.
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