Introduction to Biophysics Week What is Biophysics.pdf

Introduction to Biophysics Week: What is Biophysics? Biophysics is a thriving discipline, as is e vident by the breadth and depth of the science that is bein g presented at the Biophysical Society Annual Meetin gs and published in Biophysical Journal . Y et, biophysics als o has an identity problem\u2014due to the wide range of research topics that properly fall under the general rubric of biophysics\u2014and biophysicists often \ufb01nd themselves challe nged when asked to describe what the term actually represents. Biophysics, as a distinct discipline, can be traced to a \u2018 \u2018gang of four\u2019 \u2019: Emil du Bois-Reymond, Ernst von Br \u20ac ucke, Hermann von Helmholtz, and Carl Ludwig \u2014all four b eing physicians and the former three being students of the great German physiologist Johannes M \u20ac uller , who, in 1847, got together to develop a research program based on the rejec- tion of the, at the time, prev ailing notion that living animals depend on special biological laws and vital forces would differ from those that operate in the domain of inorganic na- ture. In contrast, the group sought to explain biologi cal function using the same laws as are applicable in the case of physical and chemical phenomena . As stated by Ludwig and quoted from Crane\ufb01eld ( 1 ) \u2018 \u2018W e four imagined that we should constitute physiology on a chemico-ph ysical founda- tion, and give it equal scienti\ufb01c rank with Physics. \u2019 \u2019 They coined the term \u2018 \u2018organic physics, \u2019 \u2019 and du Bois-Reymond stated, in the introduction to his seminal work Unt ersuchun- gen \u20ac uber thierische Elektrizit \u20ac at ( http://vlp.mpiwg-berlin. mpg.de/library/data/lit28623/index_html?pn ¼ 1&ws ¼ 1.5 ), that (translation by Crane\ufb01eld ( 1 )) \u2018 \u2018it cannot fail that . physiology . will entirely diss olve into organic physics and chemistry . \u2019 \u2019 It did not quite work out that way and, despite the scien- ti\ufb01c accomplishments of these four, in particular Helmholtz and Ludwig, the program faltered. In 1982, when Karl Pear- son introduced the term \u2018 \u2018Bio-Physi cs\u2019 \u2019 in The Grammar of Science ( 2 ) to describe the science that links the physi cal and biological sciences, he also noted \u2018 \u2018This branch of sci- ence does not appear to have adv anced very far at present, but it not improbably has an important future. \u2019 \u2019 Indeed, more or less as Pearson wrote these pithy com- ments, Julius Bernstein ( 3 ) published his descrip tion of a possible mechanistic basis for the de velopment of trans- membrane potential differences based on studies by Ner nst and Planck on electrodiffusion. A fe w years later , Archibald V . Hill publishe d his seminal work on the Hill equation ( 4 ). Both studies are reminiscent of the 1847 group\u2019 s program and serve as prototypical examples of biophysics as the quantitative study of b iological phenomena. The mainstay of biophysical research in the early part of the twentieth century was neuro - and muscle physiology , disciplines that lend themselves to quantitative analysis and in which most of the in vestigators had trained in biology or medicine. In the latter half of the cent ury , an increasing number of biophysicis ts were trained in chemistry , physics, or mathematics, which led to the development of the modern generation of optical and electron microscope s, \ufb02uorescent probes (whether small molecules or genetically encoded proteins), synthetic oligonucleotides, magnetic resonance and diffraction methods, as well as the computational methods that, by now , hav e become indispensable tools in biophysical research. Y et, we continue to face the question, \u2018 \u2018What is biophysics?\u2019 \u2019 Maybe the best way out of this conundrum is to heed the advice of A.V . Hill, who long ago noted that \u2018 \u2018the employment of physical instruments in a biological laboratory does not make one a biophysicist, \u2019 \u2019 rather it is \u2018 \u2018the study of biol ogical function, organization, and structure by physical and physicochemical ideas and methods\u2019 \u2019 ( 5 ). It is the mindse t\u2014the focus on the impor- tance of providing a quantitative, theoretically based, anal- ysis of the problem under study\u2014that is important ! This emphasis on theory and quantitation is central to the meth- odological developments that provide the foundation for current biophysical rese arch. It also leads to a possible answer to question in the title\u2014biophysic s is the quantita- tive approach to the study of biological problems. Indeed, we are beginnning to ful\ufb01ll the vision of the \u2018 \u2018gang of four\u2019 \u2019 in 1847, based in large part on the emerging conver gence of increasingly sophi sticated quantitative experimental approaches together with computational studies, such as molecu lar dynamics simulations that use classical and statistical mechanics to explore protein func- tion. Some of these developments are summari zed in the following series of articles which has been compiled by the Biophysical Society\u2019s Publications Committee in conjunction with Biophys ics W eek to provide an overview of the state of biophysical studies and to heig hten the aware- ness of the importance of biophysics as a central discipli ne in modern biological research. One of the driving forces in current biophysical research has been the development of nov el microscopes that make it possible to visualize structures at spatial resolutio ns that transcend the diffraction barrier . The diffraction barrier limits the ability of optical microscope s to distinguish among points that are separated by (lateral) distances less than one-half the wav elength of the light that is used to http://dx.doi.org/10.1016/j.b pj.2016.02.012 *Correspondence: sparre@med.cornell.ed u Chair, Biophysi cal Society\u2019 s Publications Committee Ó 2016 by the Biophysical Society 0006-3495/16/03/0001/3 Biophysical Journal Volume 110 March 2016 E01\u2013E03 E01 visualize the specimen of int erest. Another force in biophys- ical research has been the development of (usually) \ufb02uores- cent probes that make it possible to visualize living cells, including cells deeply emb edded in tissues and even li ve an- imals. Many of the exciting advances in optical microscopy are summarized in the contribution by Rick Horwitz \u2018 \u2018Cellular Biophys ics. \u2019 \u2019 Genetically encoded \ufb02uorescent probe s have pro ven to be particularly powerful tools because they can be targeted to speci\ufb01c cells and intrac ellular organelles, thereby facili- tating exploration of problems that were beyond the capa- bility of chemical probe s. T argeting probes to speci\ufb01c cell types in a tissue means that investigators can study li ving cells and tissues at high spatial and temporal resolution and can use focused light impulses to manipulate genetically encoded targets, thereby manipulating cell function at the whole organism level. In this latter approach, the role of the microscope has change d fundamentally from bein g a tool to observe biological function to becoming a tool to manipulate biological function. The discoveries that led this important and novel \ufb01eld, coined optogenetics, are dis- cussed in the contribution by Adam E. Cohen \u2018 \u2018Optoge- netics: T urning the Microscope on Its Head. \u2019 \u2019 The power of optical microscopy also enables researchers to probe the forces that underlie mac romolecular function at the single-molecule level. The ability to visualize the function and motions of individual molecules leads to qual- itatively dif ferent studies than are possible using measure- ments on ensembles of molecules, which only report on the average behavior of the ensemble. For example, if you want to elucidate the mechanics of human locomoti on, it would not be very helpful to observe the movement of mara- thon runners across the V errazan o-Narrows Bridge in the New Y ork Marathon; you would need to focus on the motio n of individual runners to understand the sequence of events. Proteins and nucleic acids similarly undergo complex mo- tions that best are examined at the single-molecular level, and T aekjip Ha\u2019 s article \u2018 \u2018Probing Nature\u2019s Nanomachines One Molecule at a Time\u2019 \u2019 describes some of the exciting de- velopments in this rapidly expanding \ufb01eld. The advances described by Horwitz, Cohen, and Ha build on developments in optical microscopy; equally important advances hav e taken place in electron microscopy . A new generation of cryo-electron micro scope s with direct electron detectors enabl es atomic resolution studies on mac romolec- ular structures based on images of thousands of individual molecules. This approach differs fundamentally from the analysis of crystal diffraction patterns or distanc e con- straints obtained in nuclear mag netic resonance studies, and the novel de velopments allow researchers to determine the atomic resolution structures of macromolecul es that cannot be crystallized, which has led to a revolution in struc- tural biology . Edward H. Egelman\u2019 s \u2018 \u2018The Current Revolu- tion in Cryo-EM\u2019 \u2019 traces the key methodological advances that underlie the current revolution, which depend not only on the advances in the hardware, but also on adv ances in the software that is required to process the large amount of data needed for the elucidation of atomic resolutio n structures. As noted in T aekjip Ha\u2019 s contribution, proteins are nano- scale machines that underlie much of what we consider to be characteristic of life. Becaus e normal life (health) is so crit- ically dependent on the proper function of these nanosc ale machines, it often has been assumed that proteins need to be folded into well-de\ufb01ned structures to accomplish their in- tended functions; this turns out to be incorrect ! Over the last 20 years or so, it has becom e apparent that many important proteins have amino acid sequences that cannot fold int o conventional folded structure s. This has led to a funda- mental revision of the relation betwee n protein sequence, structure, and function. These developments are summa- rized by H. Jane Dyson in \u2018 \u2018Intrinsi cally Disordered Proteins. \u2019 \u2019 Somewhat surprisingly , many intrinsically disor- dered proteins, or disorder ed regions within otherwise well- folded proteins, turn out to function as key elements in protein interaction networks. Moreover, because these se- quences are disordered, they are susceptible to chemical modi\ufb01cation that often is critical for normal (as well as abnormal) function, which makes them useful for designing targeted interventions. Many human diseases result from mutations that alter the sequence and thus the function of important proteins. In some cases, the changes in function can be understood \u2018 \u2018simply\u2019 \u2019 from how a given mutation alters the functi on of the cells that host the protein; in other cases, it becomes necessary to understand ho w the mutation alters the function of systems of interacting cells. This change in thinki ng, from focusing on the intrinsic propert ies of, for example, proteins or cells in isolatio n, to exploring the complex inter- actions that occur at the molecular, cellular , and system levels becom es important for understanding not only how normal body function is maintained, but also how human disease develops. In their article \u2018 \u2018Inherite d Arrhythmias: Of Channels, Currents, and Swimming\u2019 \u2019 Maura M. Zylla and Dierk Thomas discuss how inherited arrhythmias are best understood through such multiscale approache s, using the fam ily of diseases that are lumped under the rubric, the long QT syndrome, which may cause sudden cardiac death due to the development of fatal arrhythmias. Most cases of sudden cardiac death are due to degenerative changes in the coronary vessels. A small fraction, how- ever , results from change s in the function of a family of membrane proteins, the ion channels, that are responsible for normal cardiac rhythmicity . These changes in rhyth- micity can lead to sudden loss of conscious ness and even death\u2014often in young people. As noted by Zylla and Thomas, an abnormal increas e in the duration of the electri- cal impulses (the action potenti als) that drive the heart and pump blood throughout the body may paradoxically lead to an, often sudden , increase in heart rate that may Biophysical Journal 110(5)E01\u2013E03 E02 Editorial compromise the heart\u2019 s ability to move blood through the body . Reduced blood \ufb02ow to the brain may lead to the sud- den unconsciousness and death that are char acteristic of this class of diseases. This is a situation where it becomes impor- tant to be able to sort through the underlying problems at many different level s of complexity , ranging from isolated channels to cells to how the cells are organized and intera ct in the tissues of the heart. Once these intera ctions are under- stood through biophysical analy sis, it becomes possible to develop rational therapies. The i mp orta nc e o f mul ti sc al e app ro ac he s to u nd er st an d both no rmal an d abno rm al body fu nc tion is de velop ed fu rthe r by Andr e w D. McCull oc h in \u2018 \u2018Syste ms Biop hy sics : Mul tisc ale Biop hysi cal Model ing of Or gan Syste ms. \u2019 \u2019 Focus ing ag ain on the heart, Mc Cull oc h emphas iz es ho w it become s impo r- tant to un ders tand th e syst em at man y dif ferent , mutual ly in - tera ctin g, le vels of comp le xity . The elec tric al syst em tr igge rs the co ntra ctio ns of the cardia c ce lls th at ma ke th e hear t an ef\ufb01ci en t pump ; ho wev er , to full y unde rsta nd th e he art\u2019 s mech anic al perf or manc e, it is ne cess ar y to deli neat e the coup ling be tween the at ria an d th e v entr ic les as we ll as th e dyna mics of th e hear t val v es and th e bloo d \ufb02o w throug h the co rona ry ci rcul atio n. P robl ems mu st be ap pr oach ed from th e mo lecu lar to the tissue lev el an d th en coup led with th e electr ic al and mech an ica l perfor ma nce to de velop an unde rsta nd ing of over all he ar t func tio n, wh ich ca n be acco mpli shed th ro ugh mult is cale co mput at iona l mode ling . The \ufb01nal contribution in this series, \u2018 \u2018How V iruses Inv ade Cells, \u2019 \u2019 is by Fred Cohen, who describes the mechanism (s) by which important viruses, such as in\ufb02uenza, HIV , and Ebola, are able to infect cells and \u2018 \u2018highjack\u2019 \u2019 cellular pro- cesses. These cellular proce sses would normally support the regulated turnover of membrane component s as well as cell division, but they are di verted to produce proteins en- coded by the virus genome, which is necessary for viral replication and exit from the cells, lea ding to the infection of other cells. A key \ufb01rst step in viral infection is to insert the viral genome into the cell that is being attacked. This often happens through a series of processe s that begin with viral uptake into lysosomes that normally are charged with hydrolyzing ingested materials. Once in the lysosome, the viral en velope fuses with the lysosomal membrane, a process that is activated by the very acid environment in the lysosome, and the viral genetic enters into the host cell\u2019 s cytoplasm. As noted by Cohen, the most reliable way to pre- vent infection is to eliminate viral entry . T o do so, howe ver , requires understandin g the underlying mechanisms of this process, which depends on the sophistica ted methods that have been described in other contributions in this collection. The contributions in this collection are not intende d to provide a comprehensive overvie w of the excitement and importance of biophysi cal research. Rather, they provide ex- amples of how one can use the power of the biophysical approach\u2014the methods and analysis, the emphasi s on quan- titation, and the conceptual approach to problem solving\u2014 to understand important questions related to both normal and abnormal biological functi on, including huma n disease . Olaf S. Andersen 1 , * 1 Department of Physiolo gy and Biophysics, W eill Medical College of Cornell University , New Y ork, New Y ork REFERENCES 1. Crane\ufb01eld, P . F . 1957. The organic physics of 1847 and the biophysics of today . J. Hist. Med. Allied Sci. 12:407\u2013423 . 2. Pearson, K. 1900. The Grammar of Science, 2nd Ed. Adam and Charles Black, London . 3. Bernstein, J. 1902. Untersuchungen zur Thermodynamik der bio- elektrischen Stro ¨ me. Arch f. Physiologie. 92:521\u2013562 . 4. Hill, A. V . 1910. The possible effects of the aggregation of the molecules of hæmoglobin on its dissociation curves. J. Physiol. 40:i v\u2013vii . 5. Hill, A. V . 1956. Why Biophysics? Science. 124:1233\u20131237 . Biophysical Journal 110(5)E01\u2013E03 Editorial E03

Introduction to Biophysics Week What is Biophysics.pdf

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