new mitochondrial protein structure - form and function!

 

My brother who is a graphic designer in Chicago came across this and sent it to me over the weekend. 

What I loved about this discovery is that it connects form and function. The way the many proteins of cellular respiration pathways physically fit together in the mitochondrial inner membrane causes the membrane to bend, helping to explain how convoluted the inner membrane is. This bending helps maximize the surface area of the inner membrane within the bounds of the smooth outer membrane. 

And I didn't know this, but apparently an earlier discovery was that the ATP synthase polymerizes into a helical fiber! 

Variations on the theme of contractile rings

 

 

Our Cell Division lesson covered how at the end of mitosis an actomyosin contractile ring assembles in location and with a timing dictated by the anaphase spindle.

Actomyosin rings also form in other contexts, such as when a pocket of cytoplasm buds off from a germline syncytium to form an oocyte.

Recently-graduated PhD student Jack Linehan from my lab (now doing a postdoc at NCSU) measured the size and speed of different actomyosin rings, and measured how the amount of ring proteins changed over time (were retained and compacted or were shed off). He then applied these measurements to a mathematical model of a ring made of contractile gel. The model could only fit the different experimental measurements if we made one of the model parameters different for the different kinds of rings.

That’s exciting because it makes a specific prediction about something that might be different across nature’s variations on the theme of actomyosin rings. We hope to make experimental measurements to test that prediction, soon.

Jack first posted a preprint* and has now published, in Molecular Biology of the Cell, about variations on the theme of contractile ring closure. Anonymous referees read our paper and submitted their opinions and recommendations to a scientist who’s an editor for Molecular Biology of the Cell. The editor said if we made the changes the referees suggested, he could probably accept it for publication. We prepared our revisions, which the editor and one or two of the referees evaluated, and then the paper was accepted!

 

 

* pre-prints are manuscripts shared globally via the open repository BioRxiv. "Open" means anyone can access the contents - they don't have to pay $35 per paper they want to read, like for lots of for-profit journals; their university library doesn't have to pay hundreds or thousands of dollars for access to the repository like they have to for journals.

Pre-prints are not peer-reviewed. Peer review is the process by which 2, 3, or 4 (or sometimes more) usually-anonymous "peers" (research faculty at universities around the world) evaluate a manuscript according to the standards of a the journal where they paper is being considered, and their own experience and standards. They give a yes, no, or revisions required answer, and usually many comments ranging from typos to perceived conceptual errors to recommended extensions of the work. The journal editor summarizes all the comments and tells the authors what they need to do to get accepted and published. Sometimes they just reject the paper and the authors need to try somewhere else.

Pre-prints can receive comments and suggestions, but people don't do that very much yet. This could help prepare the manuscript for anonymous peer review.

Peer-reviewed publication is still the gold standard for showing you've advanced a field, but pre-prints allow the community to see what you've done even before that long process is complete.

recent research on focal adhesions

 

Rae Cho here at UNC is working on focal adhesions in muscle cells, and considering what they call a "radical form of post-translational modification." 

Remember proteolysis from the Signaling lesson about the Delta-Notch signaling cascade? Professor Cho is studying proteolysis in the context of cell-substrate adhesion. It's a compelling way to make a irreversible or slowly reversible change such as those needed for cell differentiation. 

Read more about our colleague here! They have a good sense of humor and celebrate the company of their furry friends.

Are mitochondria (not just the powerhouse of the cell but also) light sensors?!

Vision is so important to people - to most animals, really! We have specific and special eyes that collect light and code images, and a big part of our brain is dedicated to decoding that information. But the eye and optic nerve and brain are all made up of cells - so can any individual cells actually see or is vision an emergent behavior of cells, tissues and organs? When I saw this paper about vision in single cells, I as amused to learn about the hypothesis that mitochondria form part of see-ing parts of simple tiny organisms. I wondered what else was known about the evolution of sight and stumbled across this TedX talk. You might find it fun, too!

Curiosity creates cures

Want some help explaining to others how studying bacteria, or yeast, or flies can tell us something important about human health? How curiosity is an engine to important discoveries? Here's a video and a great summary from the NIH.

Cytoskeletal dynamics movies

• See beads whiz around: Actin comets and motility induced by an activator of an actin nucleator stuck onto beads
• A GFP-tagged protein that binds only to the plus ends of growing microtubules 
• Beautiful movies of cells using a microscopy trick that we didn't talk about in the course (lighting up cells with a super-thin sheet of light coming in from the side) and tumor cells expressing a GFP-tagged polypeptide that binds actin filaments, viewed like this

Cystic fibrosis and drug development

Trikafta is a 3-part drug that helps deltaF508 cystic fibrosis patients. Trikafta was approved by the FDA in 2019 based on studies testing efficacy and safety [1],[2]. The figure below illustrates mechanisms of action for a previous 2-part drug and the new 3-part drug. 

Bad news though: the drug costs more than $300,000 per year (so research on more cost-effective solutions is critically important). Developing drugs like these costs a lot, and drug companies need to recoup costs and make a profit to justify investing in possible new drugs, so the FDA gives companies a 5-7 year monopoly when a drug is developed, before generic versions of drugs can be sold. The complex issues involved are covered well, I think, here.

You can find info about cystic fibrosis from the NIH, and current clinical trials here.

Here's an old but really interesting article about Cystic Fibrosis, and a source for up-to-date information on the disease and its effects on patients.

Kizzmekia Corbett, a Tar Heel and a science hero

"Kizzmekia Corbett had gone home to North Carolina for the holidays in 2019 when the headlines began to trickle in: A strange, pneumonialike illness was making dozens of people sick...."

Among the scientists we have to thank for the COVID vaccines that were transformational in the pandemic is one person who played a central role in the development of RNA-based vaccines, Dr. Kizzmekia Corbett.

Dr. Corbett grew up near Chapel Hill, worked in a UNC lab for a summer in high school, and then moved back and forth between North Carolina and the DC/Baltimore area as a researcher: she was a student in the famous Meyerhoff Scholars Program at UMBC, then did her PhD at Carolina, and then moved to the National Institutes of Health.

At the NIH, Corbett became the scientific lead of the Vaccine Research Center's COVID-19 team that developed mRNA-based vaccines by making use of the Cryo-EM structure and her and colleague's previous work on MERS virus to design an mRNA vaccine rapidly. Corbett and colleagues discovered that the mRNA vaccines worked in mice and in primates, leading to the Moderna and Pfizer mRNA vaccines that transformed the pandemic.

December 2020: The efficacy of the Moderna (see p. 30) and Pfizer (see p. 58) mRNA vaccines was shockingly good! Whew!

Now she's a professor at Harvard, running a lab that studies vaccines and the immune system, to inform the development of new vaccines including (fingers crossed) a vaccine that might work against all SARS-COV-2 virus variants. She's been active on social media, which has given people an almost-live, inside view of what must be a fascinating path.

Here's a general-interest interview with then-NIH chief Francis Collins...

... and I recommend especially another interview that spans from her initial interest in science to some more in-depth virology:

 

Try your hand at some simple bioinformatics

You can try some simple bioinformatics yourself if you like. Here are two things to try:

 

(1) Get a gene sequence and see what predictions can be made from it. I recommend starting by thinking of a protein or gene of interest. Find a disease gene in a news article for example. Then get the protein sequence. You can find sequences here – type in the name of any protein or gene (here for example is a resident ER protein, i.e. a protein that stays in the ER). Click on a specific protein's name and the sequence will be at the bottom of the next page. Click "FASTA" near the top of this page to get the sequence in a simpler format, and copy and paste that sequence into any of the programs below to try them out.

To start with, you might try a program that can predict the arrangement of transmembrane proteins based on sequence. The program, described in more detail than most people will want to see here, uses rules deduced by biologists, and was then fine-tuned with an artificial intelligence algorithm, training the program using transmembrane proteins with known orientations.  There is a similar program that can predict where in a cell a protein will end up.  

Then you can try other predictions that can be made based solely on sequence by searching online for other predictor tools.

(2) See how little a well-conserved protein has changed through evolution. Let's look at the current versions of beta-tubulin from yeast and human, and see how similar they are. Try this: copy the text of the yeast beta-tubulin sequence from here (from MREI... to the end of the protein's sequence), then paste it into the Enter Query Sequence box here, under Choose Search Set, for Database choose non-redundant protein sequences (nr) and next to Organism, type "human" and then select human from the dropdown menu that appears ('human' or 'humans'). Then click BLAST at the bottom. The page will automatically update for seconds or minutes, depending on how busy servers are. When it's done, you'll see the results in a tab marked Alignments. You'll see the sequence you queried (the yeast beta-tubulin) and the subject sequence – the closest protein sequence that it could find among all known human proteins. In between is a list of identical amino acids, and + signs for similar amino acids (similar based on charge, etc). Tubulin, actin, and histones are remarkably well conserved proteins – they've had very few changes across hundreds of millions of years of evolution. If you try the exercise with other kinds of proteins, you'll see that only parts of them are well conserved across diverse organisms, or that some don't exist in certain organisms.

More about Bioinformatics at Wikipedia.

(image: a 7-transmembrane protein from Wikimedia Commons)

Nobel Prizes

UNC's Aziz Sancar on a Turkish postage stamp

The Nobel Prize web site has great, clear explanations of the important discoveries that have been recognized with the award, along with the key experiments that led to these discoveries. The newest ones have both introductory and advanced explanations as pdf files. 

The Nobel Prizes are announced each October. Most of the ones below were awarded for discoveries that we're discussing in class.

• 1974: George Palade and the secretory process
• 1986: Cell-cell signaling by growth factors 

• 

  Good spot for a selfie!
  Smithies' old UNC parking
  spot on Medical Drive
  

  
  

  1992: Reversible protein phosphorylation as a biological switch 
• 1997: Certain proteins (prions) can act as infectious agents 
• 1999: Discovery of signal sequences for protein sorting 
• 2001: The cell cycle
  
• 2007: Oliver Smithies at UNC! (Oliver passed away in 2017).
• 2008: GFP
• 2012: G protein-coupled receptors in cell communication
• 2014: Super-resolution microscopy
• 2015: UNC's Aziz Sancar for DNA repair mechanisms! Go Heels!
• 2017: CryoEM
• 2020: CRISPR - Jennifer Doudna (pictured below) will be speaking at UNC on March 26. If you want to see her and hear the talk, go early for a good seat!

Charpentier and Doudna, from a great video about their work on CRISPR and their 2020 Nobel Prize.

Turning a molecular wheel with a flow of protons

(image source)

A scientist's story of first hearing Peter Mitchell's proposal that a concentration gradient of protons was the energy source for ATP synthase. 

I recommend reading this starting in the middle, with "In 1955..." (highlighted, second sentence of the 3rd paragraph) and then looping back to the beginning of the article afterwards.

"I remember thinking... that I would bet anything that ATP synthesis didn’t work that way."

Mitchell was an unusual scientist:

"For much of his career he worked in his own lab in a... house... his research funded in part by a herd of dairy cows." (source)

In this video, see how ATP synthase works with key molecular details gained in part from solving protein structures in different states (ATP-bound, ADP-bound states etc) mostly from John Walker's lab in Cambridge, England. Walker shared the Nobel Prize for deciphering the structure of ATP synthase.

 

* EVERYTHING ABOVE WAS POSTED AFTER THE 1ST EXAM *

.

Sickle cell anemia

Learn more about sickle cell anemia, the most common inherited blood disorder in the US, at an NIH web site or the Sickle Cell Disease Association of America web site.

Here's a NY Times story about recently approved gene therapy (for those interested in science writing, the author Gina Kolata is a great writer who tells engaging stories while reliably getting the science right, and she has several books out). Gene therapy is an important step forward, but sadly, as this story covers, the current cost of gene therapy makes it unavailable to many patients, and as these stories cover, gene therapy patients have faced some challenges to date.

Here's an earlier 22-minute radio story about the first US patient whose bone marrow cells' genes were edited using CRISPR. 

Get an idea of what else is being tried right now toward cures and toward treatments for symptoms by seeing current clinical trials.

Brownian motion simulation

Try out this simulator to get an intuitive sense for how Brownian motion works. Slide the "energy" slider to the right to see what happens at higher temperatures. And be sure to "drag to see what's actually going on". Much of the theory here was worked out by Einstein. Here's a translated version of Einstein's original 1905 publication that began to explain what causes Brownian motion.

Dorothy Crowfoot Hodgkin

Read about Dorothy Crowfoot Hodgkin here, on Wikipedia, and in her biography.

(Image: British postage stamp honoring Hodgkin)

At the beginning of the course, I explained that the science we are discussing intersects with other aspects of life in many ways, and that I'd discuss those ways on occasion. For anyone interested in how women have been portrayed in science journalism, here's a headline from when Hodgkin won the Nobel Prize, and another, plus a newer checklist developed to help science journalists think clearly about whether their writing rehashes cliches at the expense of explaining the science and the scientist's achievements. Here you can read a little detail about the exclusion of women in research discussions in the time and place where Hodgkin was making discoveries. 

How many diseases are linked to specific genes? How many disease genes are there?

(image credit)

Check back on the links below and watch the numbers go up throughout the course!

• How many diseases have genes associated with their malfunctions? Here is a periodically-updated list. As of 15 years ago (Jan 27, 2011), 2949 diseases were known with "Phenotype description, molecular basis known: Total". Today (Jan 26, 2026) it's 7091 diseases – an average increase of nearly a new one discovered per day!
• How many disease genes are there? See "Total number of genes with phenotype-causing mutation" here. As of today (Jan 26, 2026) it's 5045 genes.  

Identifying a gene associated with a disease can be a big step toward developing both diagnostics and treatments. What kinds of genes are being discovered now? HERE is a link to news stories on some discoveries made recently. HERE's how they're discovered.

The earliest snowflake images

In 1885, Vermont farmer Wilson Bentley attached a camera to a microscope and became the first person to successfully photograph an individual snowflake crystal.

"...it was my mother who made it possible for me, at fifteen, to begin the work to which I have devoted my life. She had a small microscope which she had used in her school teaching. When the other boys of my age were playing with popguns and slingshots, I was absorbed in studying things under this microscope: drops of water, tiny fragments of stone, a feather dropped from a bird's wing, a delicately veined petal from some flower. But always, from the very beginning, it was the snowflakes that fascinated me most." -from a 1925 interview with Bentley

Henrietta Lacks

Learn more about Henrietta Lacks at her Wikipedia page. Below, historian and filmmaker Henry Louis Gates talks about Henrietta Lacks and the history of medical consent and race.

About the book about Lacks that I mentioned in class: "...the science end of this story is enough to blow one's mind... But what's truly remarkable... is that we also get the rest of the story, the part that could have easily remained hidden had she not spent ten years unearthing it: Who was Henrietta Lacks? How did she live? How she did die? Did her family know that she'd become, in some sense, immortal, and how did that affect them?" -Jad Abumrad, Radiolab

There's a movie too.

Images from microscopes day

Our images from microscope day!

Amazing images from microscopes

The Nikon Small World web site has some stunning images and videos.

Image: Growing tip of a red algae by UNC's own Dr. Nat Prunet. Go Heels! See this and other images from UNC here.

Breaking the resolution limit of light microscopy

image credit: HHMI

Here's a photo of the original PALM microscope in the living room where it was developed, and a story about this and related technologies. The Wikipedia page on super-resolution microscopy discusses PALM and several other tricks for breaking the limit of resolution for light microscopy, and this article is a nice description of the challenges and multiple clever solutions to improving resolution beyond the usual limit.

source

"...that’s where we learned about photoactivatable fluorescent proteins.... it became obvious to Harald and me that this was the missing link for the idea that I had pitched after I left Bell: we could isolate a few molecules at a time by activating limited subsets of photoactivatable proteins. It seemed so easy."

"...We were both unemployed, but Harald had some of his equipment from Bell [Labs]..."

-from Betzig's Nobel speech

Xiaowei Zhuang's lab developed a similar method, called STORM, around the same time as PALM was developed. See "STORM image gallery" at her lab web site for some super-resolution images. 

 

Struggling with your grades? Fear not!

Watch the 45 seconds between 1:45 and 2:30 to see how Chemistry Nobel Laureate Marty Chalfie (of Green Fluorescent Protein fame) did in Chemistry classes in college.

Louis Pasteur and his home

Louis Pasteur's old house is now a museum, currently under renovation through 2028. You can see it well documented here. Pasteur is buried in the basement, in an elaborate crypt (pictured here). 

Microns, nanometers, etc.

Powers of Ten, a classic Charles & Ray-Bernice Eames film on grasping the sizes of things from human scale out to the then-known universe, and back in to subatomic particles.

More images from Robert Hooke's Micrographia

Here's the whole book.

Hooke's book begins with an apology to the King of England, for, well, discovering things.

Hooke's methods for immobilizing some of the insects were creative:

...I gave it a Gill of Brandy, or Spirit of Wine, which after a while e'en knock'd him down dead drunk, so that he became moveless...

Hooke's engraving of a head of a hoverfly, from Micrographia

My favorite of van Leeuwenhoek's letters, with a surprise ending

"Concerning the Worms in Sheeps Livers, Gnats, and Animalcula in the Excrements of Frogs" (van Leeuwenhoek, 1700)

In this letter, he describes finding microscopic life in frog poop. I especially like the surprise ending in the last 3 paragraphs – starting, "On the fifth day the Frog had dung'd again...." on the bottom of page 517. Scientific papers never end like this.

Google on van Leeuwenhoek's 384th birthday

A popular book about cell biology

A great, vivid exploration of some fascinating topics in cell biology. See the "Read sample" button on the left side of this page to read parts of the book now. Also available as an audiobook.