Biomolecule Imaging Pioneers Share Nobel Prize

Today, the Royal Swedish Academy of Sciences has decided to award the Nobel Prize in Chemistry 2017 to Jacques Dubochet (University of Lausanne, Switzerland) and Joachim Frank (Columbia University, New York, USA), and Richard Henderson (MRC Laboratory of Molecular Biology, Cambridge, UK). The award is given "for developing cryo-electron microscopy for the high-resolution structure determination of biomolecules in solution"

Cool microscope technology revolutionises biochemistry

We may soon have detailed images of life’s complex machineries in atomic resolution. The Nobel Prize in Chemistry 2017 is awarded to Jacques Dubochet, Joachim Frank and Richard Henderson for the development of cryo-electron microscopy, which both simplifies and improves the imaging of biomolecules. This method has moved biochemistry into a new era.

A picture is a key to understanding. Scientific breakthroughs often build upon the successful visualization of objects invisible to the human eye. However, biochemical maps have long been filled with blank spaces because the available technology has had difficulty generating images of much of life’s molecular machinery. Cryo-electron microscopy changes all of this. Researchers can now freeze biomolecules mid-movement and visualize processes they have never previously seen, which is decisive for both the basic understanding of life’s chemistry and for the development of pharmaceuticals.

Electron microscopes were long believed to only be suitable for imaging dead matter, because the powerful electron beam destroys biological material. But in 1990, Richard Henderson succeeded in using an electron microscope to generate a three-dimensional image of a protein at atomic resolution. This breakthrough proved the technology’s potential.

Joachim Frank made the technology generally applicable. Between 1975 and 1986 he developed an image processing method in which the electron microscope’s fuzzy two-dimensional images are analysed and merged to reveal a sharp three-dimensional structure.

Jacques Dubochet added water to electron microscopy. Liquid water evaporates in the electron microscope’s vacuum, which makes the biomolecules collapse. In the early 1980s, Dubochet succeeded in vitrifying water – he cooled water so rapidly that it solidified in its liquid form around a biological sample, allowing the biomolecules to retain their natural shape even in a vacuum.

Following these discoveries, the electron microscope’s every nut and bolt have been optimised. The desired atomic resolution was reached in 2013, and researchers can now routinely produce three-dimensional structures of biomolecules. In the past few years, scientific literature has been filled with images of everything from proteins that cause antibiotic resistance, to the surface of the Zika virus. Biochemistry is now facing an explosive development and is all set for an exciting future.

About the Nobel Laureates

Jacques Dubochet, born 1942 in Aigle, Switzerland. Ph.D. 1973, University of Geneva and University of Basel, Switzerland. Honorary Professor of Biophysics, University of Lausanne, Switzerland.
www.unil.ch/dee/en/home/menuinst/people/honorary-professors/prof-jacques-dubochet.html

Joachim Frank, born 1940 in Siegen, Germany. Ph.D. 1970, Technical University of Munich, Germany. Professor of Biochemistry and Molecular Biophysics and of Biological Sciences, Columbia University, New York, USA.
http://franklab.cpmc.columbia.edu/franklab/

Richard Henderson, born 1945 in Edinburgh, Scotland. Ph.D. 1969, Cambridge University, UK. Programme Leader, MRC Laboratory of Molecular Biology, Cambridge, UK.
www2.mrc-lmb.cam.ac.uk/groups/rh15/

What can we use from this in teaching undergraduate A&P?

• If you talk about imaging molecules in your course, this could be a way to garner student interest—considering that this is a current and ongoing effort in science. I always have a brief "shape is important in biological chemistry and here's what we can see with current tools" because they're going to see all those little odd-shaped rutabaga blobs in illustrations in their textbooks.


• If you bring up microscopy in your course, perhaps describing the types of microscopy, adding a bit of info on this could help show students that microscopy is still evolving—in exciting ways.


• Consider using the annual Nobel Prize announcements as a springboard to discuss the process of scientific discovery. 


• Consider mentioning the other major awards for scientific achievement and discuss what the judges seem to value most about scientific discoveries. The Nobel Prize is the one everyone has heard of, so it's a great place to start.


• Use the Nobel Prizes (and other awards) over time as a way to keep students aware of the history of, and progress, of human biology. One could also address the global diversity of laureates.  Or the lack of other kinds of diversity among laureates.

Want to know more?

Popular Information 

• my-ap.us/2hNGb1D 

Scientific Background

• my-ap.us/2hPtKm0

Images

Image - 3D structures (pdf 1.4 MB)

• © Johan Jarnestad/The Royal Swedish Academy of Sciences
• my-ap.us/2hNUq6o

Image - Blobology (pdf 8.5 MB)

• © Martin Högbom/The Royal Swedish Academy of Sciences
• my-ap.us/2hLMaDV

Image - Dubochet's preparation method (948 kB)

• © Johan Jarnestad/The Royal Swedish Academy of Sciences 
• hmy-ap.us/2hPtYJS

Image - Frank's image analysis (pdf 1 MB)

• © Johan Jarnestad/The Royal Swedish Academy of Sciences
• my-ap.us/2hMkU8i 

Cool Animations (literally)

Structure and gating of the nuclear pore complex

• Eibauer M, Pellanda M, Turgay Y, Dubrovsky A, Wild A, Medalia 
• my-ap.us/2hMolMe
• my-ap.us/2hKWxbd

Ion gating in the sarcoplasmic reticulum membrane

• Samsó M, Feng W, Pessah I, Allen P
• my-ap.us/2hLJCWg

Antibody structure

• Zhang L, Ren G
• my-ap.us/2hLQp2j

Native LDL particles

• Kumar V, Butcher S, Öörni K, Engelhardt P, Heikkonen J, Kaski K, Ala-Korpela M, Kovanen P
• my-ap.us/2hO4Qms

Changes in the water and ion contents of organelles during apoptosis

• Nolin F, Michel J, Wortham L, Tchelidze P, Banchet V, Lalun N, Terryn C, Ploton D
• my-ap.us/2hMTYW4

Adapted from press release at nobelprize.org
Click each image for its source/attribution

Cytotoxic T Cell Horror Flick

Liven up your A&P class with a great video showing a gruesome attack by a killer T cell on a cancer cell. It's a fantastic bit of video microscopy produced by Cambridge University.

Okay, with the oddly soothing music score instead of a more appropriate score for the graphic violence shown in this video, it's not much of a horror flick.  Especially when you consider that it's the "bad guy" cell getting whacked.  But it is graphic and dramatic and impressive.

Just the thing to liven up a discussion of adaptive immunity, which (let's face it) can often cause a catatonic state in many students.

It's a free resource available on YouTube.

Nobel Prize 2014: Super-resolved fluorescence microscopy

The Royal Swedish Academy of Sciences has decided to award the Nobel Prize in Chemistry for 2014 to

Eric Betzig

Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA,

Stefan W. Hell

Max Planck Institute for Biophysical Chemistry, Göttingen, and German Cancer Research Center, Heidelberg, Germany

and

William E. Moerner

Stanford University, Stanford, CA, USA

“for the development of
super-resolved fluorescence microscopy”

Surpassing the limitations of the light microscope

For a long time optical microscopy was held back by a presumed limitation: that it would never obtain a better resolution than half the wavelength of light. Helped by fluorescent molecules the Nobel Laureates in Chemistry 2014 ingeniously circumvented this limitation. Their ground-breaking work has brought optical microscopy into the nanodimension.

In what has become known as nanoscopy, scientists visualize the pathways of individual molecules inside living cells. They can see how molecules create synapses between nerve cells in the brain; they can track proteins involved in Parkinson’s, Alzheimer’s and Huntington’s diseases as they aggregate; they follow individual proteins in fertilized eggs as these divide into embryos.

It was all but obvious that scientists should ever be able to study living cells in the tiniest molecular detail. In 1873, the microscopist Ernst Abbe stipulated a physical limit for the maximum resolution of traditional optical microscopy: it could never become better than 0.2 micrometres. Eric Betzig, Stefan W. Hell and William E. Moerner are awarded the Nobel Prize in Chemistry 2014 for having bypassed this limit. Due to their achievements the optical microscope can now peer into the nanoworld.

Two separate principles are rewarded. 

One enables the method stimulated emission depletion (STED) microscopy, developed by Stefan Hell in 2000. Two laser beams are utilized; one stimulates fluorescent molecules to glow, another cancels out all fluorescence except for that in a nanometre-sized volume. Scanning over the sample, nanometre for nanometre, yields an image with a resolution better than Abbe’s stipulated limit.

Eric Betzig and William Moerner, working separately, laid the foundation for the second method, single-molecule microscopy. The method relies upon the possibility to turn the fluorescence of individual molecules on and off. Scientists image the same area multiple times, letting just a few interspersed molecules glow each time. Superimposing these images yields a dense super-image resolved at the nanolevel. In 2006 Eric Betzig utilized this method for the first time.

Today, nanoscopy is used world-wide and new knowledge of greatest benefit to mankind is produced on a daily basis.

This video is a brief animation of how STED works and how it improves resolution of individual particles.

This video is a longer, more detailed presentation by one of the Nobel laureates (Hell).

What can we use from this in teaching undergraduate A&P?

• Discuss how this technology has enabled us to better visualize the chemicals and structures within our cells, enabling scientists to better understand the structure and function of cell, organelles, microbiome constituents, and other structures of the human body.


• If you do a brief run-through of the theory of microscopy—perhaps in your A&P lab—you can add a mention of this technology.  


• Your textbook or other learning resource may already have an example of this type of microscopy.


• A discussion of this  Nobel Prize could evolve into a meaningful example of how science works, including how incremental improvements in classical tools for observation expand the number of questions that can be answered.


• Use the links below (and images above) to use for a handout and/or teaching slides.

Want to know more?

Resources from Nobelprize.org

• Popular Information 
• Handout: Overview information in plain English
• my-ap.us/1rh0fAJ
• Scientific Background
• Handout: More detailed information includes references to original research articles
• my-ap.us/ZdLJ69
• Advanced Information
• Handout
• my-ap.us/1rh0dsp
• Images
• Can be used in your course
• Abbe's diffraction limit
• my-ap.us/ZR0LA8
• The principle of STED microscopy
• my-ap.us/1ncRH2C
• The principle of single-molecule microscopy
• my-ap.us/1pQbAZ4
• Biographies
• Eric Betzig, 
• U.S. citizen. Born 1960 in Ann Arbor, MI, USA. Ph.D. 1988 from Cornell University, Ithaca, NY, USA. Group Leader at Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA.
• http://janelia.org/lab/betzig-lab
• Stefan W. Hell, German citizen. 
• Born 1962 in Arad, Romania. Ph.D. 1990 from the University of Heidelberg, Germany. Director at the Max Planck Institute for Biophysical Chemistry, Göttingen, and Division head at the German Cancer Research Center, Heidelberg, Germany.
• http://www3.mpibpc.mpg.de/groups/hell
• William E. Moerner, U.S. citizen. 
• Born 1953 in Pleasanton, CA, USA. Ph.D. 1982 from Cornell University, Ithaca, NY, USA. Harry S. Mosher Professor in Chemistry and Professor, by courtesy, of Applied Physics at Stanford University, Stanford, CA, USA.
• http://web.stanford.edu/group/moerner

Diagrram cretit: Ganbaatar

Micrograph credit: Tesselkaffee

Text adapted from press release from Nobel Media

Death spreads throughout body

C. elegans

In class discussions, we talk about what happens when the body dies.  And it's always a bit tricky when the discussion gets around to the idea that not every cell dies simultaneously.

And of course, that can lead to a discussion of how tissue death occurs, even in the case of necrosis that occurs as a result of ischemia or other damage. There are certainly many mechanisms involved—quite a few of which have yet to be clarified.

Recently, researchers have brought a step closer by mapping out some of these mechanisms.  In their report (cited below), they reveal that in the gut of the C. elegans worm, calcium ions flowing into cells cause the lysosomes to burst suddenly.  And we know what that means! Intracellular destruction leading to cell death.

What causes the calcium ions to rush into the cells? Gap-junction ion-channel proteins called innexins (analogous to connexins in humans) open up and allow calcium ions to flow into one cell then the next, producing a wave of destruction along the gut.

In interesting phenomenon is that esters of anthranilic acid (formed from the amino acid tryptophan) in the lysosomes not only produce acidosis in the cytosol, they also fluoresce brightly with a bluish glow during this process of cell death.

The video below shows an amazing anterior-to-posterior wave of fluorescent blue in C. elegans worms as this "wave of death" travels along the gut wall.

Okay, now here's the kicker.  By knocking out the innexin channels, the researchers were able to stop the wave of death!  Whoa!  A cure for . . . death?!

Not so fast.  This worked in a WORM, which is not as complex as a vertebrate like the human.  And it only worked in INJURED worms, not elderly worms dying of old age.  So it won't stave off death entirely—or unusually prolong life—but it could lead to treatments for preventing or reducing necrosis that occurs as a result of ischemia and other injuries.

This information—and that dramatic video—could be an interesting addition to your class.  It ties in why it's important to understand concepts such as:

• ions
• amino acids
• ion flow into cells
• gap-junction ion channels
• lysosomes
• cell death and organismal death
• necrosis (and factors leading to necrosis)
• use of animals in research
• the intersection of basic science research and medical applications

Want to know more?

Anthranilate Fluorescence Marks a Calcium-Propagated Necrotic Wave That Promotes Organismal Death in C. elegans. 

• Coburn C, et al.  PLoS Biology 11(7): e1001613. 2013. doi:10.1371/journal.pbio.1001613
• The original research article.  Includes FREE images and PowerPoint slides you can use in your course.
• my-ap.us/19SRjOG

Glowing, Glowing, Gone: Cell Fluorescence Casts Light on How Death Spreads Throughout Body

• By Christopher Crockett. Scientific American online 2 August 2013
• Brief, less technical, article explaining that researchers have identified a key molecular pathway for animal death that may provide clues for better managing traumatic injury and disease in humans.
• my-ap.us/13MxJjs

Andrew Huxley

A few weeks ago, science lost one of its greats . . . Andrew Fielding Huxley. 

As explained in my textbooks, "The British physiologist Andrew F. Huxley (born 1917) is  largely responsible for explaining how muscle fibers contract. After making pioneering discoveries in how nerves conduct impulses, a feat for which he shared the 1963 Nobel Prize in Medicine or Physiology, Huxley turned his attention to muscle fibers. It was he who in the 1950s proposed the sliding filament model, along with its mechanical explanation of muscle contraction."

Sometimes, our students don't fully appreciate that much of what we know about basic functions of the body have been discovered only within the last few decades.  They may not realize that people alive during their lifetimes were the ones who discovered central concepts of human structure and function, such as how nerves conduct action potentials and how muscle fibers contract.

The reason I include stories of Huxley and others in both my A&P textbooks and in my classroom discussions is that I think the story of science is important in gaining deep understanding of the concepts learned in A&P.  Learning "just the facts" devoid of their context and without any understanding of how we learned what we know does not give our students what they need to navigate the ongoing evolution of our scientific understanding of human A&P.

I also like to include stories of the people who helped shape our current understanding of the body's structure and function because it reveals the diversity of backgrounds, approaches, ethnic/national origins, gender, and age of the folks who have made striking discoveries and provided critical insights. I think that helps students understand that they, too, can play a role in the progress of science.

If you want to brush up on Huxley's role in the progress of science--so that you can perhaps drop it during your classroom discussions of nerve impulses and muscle contraction--check out the resources I have provided.

Want to know more?

Sir Andrew Huxley obituary: He shared the Nobel prize for unravelling the mechanism of the nerve impulse
Anthony Tucker   
guardian.co.uk, Thursday 31 May 2012 13.05 EDT
[Nice article summarizing the life and contributions of A. Huxley]
my-ap.us/O6jMUL   

Andrew Huxley, Nobel-Winning Physiologist, Dies at 94
By DENISE GELLENE
New York Times (online) June 4, 2012
[Another comprehensive obituary of Huxley]
my-ap.us/O7flW7

Click here for a photo you can use in your course.

Video: Neutrophils to the Rescue

Have you seen this video from Science Videolab that shows fluorescent-stained neutrophils rushing toward the site of a tissue injury?

The clip actually strings together several videos showing bright green neutrophils rushing toward damaged cells in liver tissue (seen as bright red areas).  The narrator explains in simple terms what is going on and what it means in understanding what happens when tissue damage occurs.

This is a great FREE video to show your class when discussing any or all of these topics:

• WBCs in general
• Neutrophils
• Immune response
• Inflammation
• Chemotaxis

Check out the video!

http://my-ap.us/fh1Exm

Want to know more?

Intravascular Danger Signals Guide Neutrophils to Sites of Sterile Inflammation
Braedon McDonald et al.
Science 15 October 2010: Vol. 330 no. 6002 pp. 362-366 DOI: 10.1126/science.1195491
[Research article that summarizes the discovery about how neutrophils use a multistep process to navigate toward noninfectious sites of tissue injury. ]
http://my-ap.us/f5Fua6

EDITORS' CHOICE: Immunology Inflammation Response in Living Color
Kristen L. Mueller
Sci. Signal., 19 October 2010 Vol. 3, Issue 144, p. ec324 DOI: 10.1126/scisignal.3144ec324
[Editor's summary of the processes described above]
http://my-ap.us/fFfwOq

Prezi practice practicals

In my blog The Electronic Professor, I recently wrote about the Prezi alternative to PowerPoint presentations.

In a nutshell, Prezi creates large, complex sets of information that you can zoom into either at will or in a preplanned way.

As I was exploring around the Prezi presentations that have been made public, I found a great idea . . . why not use Prezi to create practice lab practicals?

My students always find it hard to get ready for practicals.  Obviously, part of the issue is the massive amount of content that we ask them to learn.  But, perhaps more imporatantly, it's hard for them to imagine the kinds of questions that they are likely to get. We set up "practice practicals" in our open lab when we can . . . and that helps a lot.  But wouldn't it be great to have an easy to access online place our students can practice for their praticals?

Well, Rob Swatski at the York Campus of Harrisburg Area Community College (York, PA) has already cracked this egg!

Take a look at his Virtual Lab Exam for muscles in A&P 1.

Virtual Anatomy Lab Exam on Prezi

You have to start clicking around and get the feel for how this practice lab practical is set up . . . but once you have the hang of it, it's amazing.  You can see how students can practice the content and also get a feel for EXACTLY the kinds of things they'll be asked to do on their practical.

Another idea that Rob came up with is shown in this presentation that introduces the microscope.  Rob uses the particular characteristics of Prezi to full advantage to produce a resource that is useful for both teaching and learning in the A&P lab.

Take a Virtual Tour of the Microscope on Prezi

Imagine how useful this sort of thing can be for

• online tests and quizzes for labs
• exploring large, complex anatomical structures in a lecture class
• virtual dissections
• student presentations
• zooming in on tissues or bone markings while teaching histology

Let's hear YOUR ideas!

Looking at cilia

 

In a recent article in The Scientist, Peter Satir points out that the cilium was the very first distinct organelle ever directly observed by scientists--van Leeuwenhoek noted their existence in the 1660s.  But we are only now starting to fully understand these amazing and vital structures.

Until only the last decade or so, we thought that cilia were organs of cell motility--period.  But as I've noted in recent editions of my textbooks (e.g. Anatomy & Physiology, p.82-83), we now know that cilia play a critical role in a cell's ability to sense its surroundings.

Not only is this sensory function useful for, well, er, mediating senses such as hearing and equilibrium, it's also critical for cells to figure where to go (and when) during embryonic development.  In fact, it's been shown that situs inversus (the condition in which internal organs are flipped in their left-right orientation) is caused by a mutation affecting the structure of the primary cilium of developing cells in the embryo.

Cilia, it turns out, are centrally involved in a lot of different cell functions.

If you want a quick and interesting review of the history of cilia from one of the pioneers in cilia research, including answers to "why do we have to learn this stuff if I'm going to be a [insert health profession here]?," then check out this article:

Eyelashes Up Close
Peter Satir
The Scientist Volume 24 | Issue 7 | Page 30 2010-07-01
[Brief, well-illustrated review of what we know about cilia so far.  Includes great graphics and useful references.]

For more FREE images of cilia you can use in your course, see The A&P Professor website's FREE Image Library of Cell Structures.
.
.

Virtual Microscope (and other FREE stuff)

Have you ever been to the Blue Histology website? Produced by the School of Anatomy and Human Biology at the University of Western Australia, and sponsored by Olympus, this site is chock full of excellent histology images (often at several magnifications) that you and your students can use for FREE.

One of the nifty features at Blue Histology is their VScope which is a virtual microscope that can help students figure out some basic things about changing magnifications, using the diaphragm, and other essential skills for light microscopy.

They assert that their VScope is not an ideal simulator of the real microscopy experience, even going so far as to intentionally mispel the title of their project as "Vurtial Microscope." And it's not ideal, especially with an old computer and slow connection speed. But it's still pretty cool and still good for some "at home" exploration when an actual microscope is not available.

Check it out at http://www.lab.anhb.uwa.edu.au/mb140/

2008 Nobel Prize in Chemistry

Just as I predicted . . . this year' Nobel Prize for chemistry has an A&P connection!

The announcement came as scheduled on October 8 . . . and the same day I notified you via a voice message at our drop.io drop . . . .

The Royal Swedish Academy of Sciences has decided to award the
Nobel Prize in Chemistry for 2008 jointly to

Osamu Shimomura,
Marine Biological Laboratory (MBL), Woods Hole, MA, USA
and Boston University Medical School, MA, USA,

Martin Chalfie,
Columbia University, New York, NY, USA

and

Roger Y. Tsien,
University of California, San Diego, La Jolla, CA, USA

"for the discovery and development of the
green fluorescent protein, GFP".

So how does this discovery relate to human anatomy & physiology? GFP (shown in the ribbon model) is that bright green stain used in all those micrographs of important structures and processes in the cell!

As the Nobel Committee states, "With the aid of GFP, researchers have developed ways to watch processes that were previously invisible, such as the development of nerve cells in the brain or how cancer cells spread."

For an example of how this protein can be used, look at Figure 16-36 in our textbook Anatomy & Physiology 6th edition. The image in part A shows GFP used to identify the location of insulin in pancreatic tissue--thus outlining the beta cells and establishing the overall structure of a pancreatic islet. Just one of many examples, of course.

And it's not just green that can be used . . . Tsien is the laureate (sharing this prize) who built on the original discovery to develop a whole palette of colors that can be used to study the human body (and other organisms).

For a nice summary, check out these FREE publications (PDF format) from nobelprize.org

Information for the public
(basic summary and significance of the discovery; has COOL multicolor photos of brain tissue)

Scientific background
(More in-depth information)

Also visit the links at the main page for this prize at http://nobelprize.org/nobel_prizes/chemistry/laureates/2008/index.html

Here's a great article from Science News (with links to previous articles related to this discovery):

Nobel Prize in chemistry commends finding and use of green fluorescent protein

By Tina Hesman Saey

Science News Web edition : Wednesday, October 8th, 2008

Here's a video explaining the reasons for awarding the prize . . .

(go directly to the blog if the video viewer does not appear in your email or news feed)

Here's a video clip explaining the concepts involved . . .

(go directly to the blog if the video viewer does not appear in your email or news feed)

For the "how-to" on how to embed these clips in your webpage, email, or PowerPoint slide, please go to the YouTube page at The A&P Professor website

Also read my article from last week regarding how I use Nobel Prize winners and their discoveries in my course . . . and how they are linked to my textbook Anatomy & Physiology.

Urine luck!

If you discuss urine sediment in your course, you might find the urine sediment images at Cornell's Urine Sediment Atlas interesting and useful.

It's set up for veterinary students primarily, but is very useful for human biology as well.

These might be good for linking to your lectures, labs, case studies, test/quiz items, wallpapering your desktop, whatever.

Check out more image sources at The A&P Professor website!

More on Microscopy of Atoms

For those who read my update on new tools to image small atoms, you may also be interested in this article:

Seeing the Smallest Atom

including a nice image you can link to in your course.

Microscopy breakthrough

Some of us spend time in our A&P course reminding our students of the chemistry that they should already know before they came to our course, right?

One of the big issues for students is being able to visualize all those tiny bits that we professors seem to be so taken with . . . molecules, ions, atoms, and so on. Of course the easiest way to visualize something is to show them a picture, eh?

Until recently, the best we could do in showing "real" pictures of atoms was a few large atoms shown in a group, as if they were eggs lined up in a carton. Now, in the July 17th issue of Nature, scientists say they have created superthin, one-atom-thick membranes made of graphene (a form of graphite) in which individual carbon and hydrogen atoms can be imaged.

Go to the World Science article at http://www.world-science.net/othernews/080720_graphene to learn more and to find a drawing of graphene and a photo of carbon and hydrogen atoms that you can share with your students.