Weekend Suitcase

“JJ had long known that something else was wrong with her — that no one should touch her blood. She had seen doctors every few months since birth and taken medicine since a plastic syringe delivered it to her mouth. “A rare blood disease,” Lee had told her, and JJ never pressed for more details.” John Cox at the Washington Post on telling a child she has HIV.

Stephen Curry reviews Photograph 51 at The Guardian, starring Nicole Kidman as Rosalind Franklin“Here is a hard problem: how to write a play about science that captures the real complexities of research while remaining accessible – and dramatic?” 

“Well, this is just plain awful: Are Antibiotics Ruining Your Libido? – The Daily Beast.  In this article, Robynne Chutkan argues that people’s sex drives may be being ruined by antibiotics.  And she presents zero evidence for this other than handwaving.” Jonathan Eisen continues to fight the good fight against microbial hype at Tree of Life.

David Dobbs at The Atlantic on the cost of misconduct in clinical trials. “A year before, in 2001, a much-publicized paper described a clinical trial that showed Paxil to be safe and effective in teenagers as well as adults. Study 329, as it became known, helped spur a huge increase in Paxil prescriptions. In 2002 alone, over 2 million prescriptions were written for children and teens, and many more for adults. (…) The study is now again in the news, as a new reanalysis of the its original dataincluding about 77,000 pages of formerly inaccessible patient records—shows that Paxil was neither effective nor safe.”

“Some readers may have never heard of The American Chestnut, but it might have been considered the counterpart to the vast conifer forests of the West, like the Douglas fir (Pseudotsgua douglasii). The American chestnut dominated eastern forests from Georgia to Maine (1 in 4 trees was a Chestnut). Until a blight, a fungus, from Asia was introduced with imported Chinese Chestnut trees. With no resistance, the blight wiped out almost all The American Chestnut trees.” Ian Street at The Quiet Branches on a new approach to an old epidemic.

Chris Stringer at Elife on our newest relative, Homo naledi, and all the questions it raises:(…) despite the wealth of information about the physical characteristics of H. naledi that this collection provides, many mysteries remain. How old are the fossils? Where does H. naledi fit in the scheme of human evolution? And how did the remains arrive deep within the cave system?”

“Light travels at around 300,000 km per second. Why not faster? Why not slower?” Sidney Perkowitz asks at Aeon.

Finding Stories: A Conversation With Daniel Davis

Something that has always interested me in science are the people that do it. Every single scientist, in every continent, has a story of how they got there, you know? Not just the really famous scientists, but all of the every-day scientists struggling, and winning, and going through the same process of groping around, trying to find a story from their data”, says University of Manchester immunologist Daniel Davis.

In The Compatibility Gene, he tells the story of how a sprawling cast of characters solved the mystery of the MHC, and explores the current research frontiers in the field, from modern immunology to neuroscience. Dr Davis spoke to us about his own journey from doing a PhD in Physics to his lab’s work at the cutting edge of imaging the immune system, and going down to a shed at the bottom of his garden to write a book.

d2 final

Illustration by Madalena Parreira.

You did a PhD in Physics?

DD I did Physics initially because I thought “what could be more fundamental than laws that are constant across the whole universe?” That’s what I should study. Then, during my PhD I did feel like it was a bit esoteric, the specific Physics that I was doing. I thought that I could have more impact if I studied Biology, and then I thought that maybe how life works is in some ways more fundamental than how Physics works. So I decided to switch, and then it was a little bit random as to which part of Biology I would go into. I actually just wrote letters to very different types of biological scientists, the kind of people that caught my attention for one reason or another. Some of the people I wrote to were in the kinds of fields that people that come from Physics often go into, like protein folding or structural biology. One of the people I wrote to was Jack Strominger in Harvard and he took me*. I thought, “it sounds great, to study how the immune system works”. It was a little bit random how I ended up in Immunology, but that’s kind of how it went.

Why did you decide to write a book for the general public?

DD In your day job in your lab, you have to be immersed in all the detail, because obviously to get a paper in your journal, you’ve got to get all the details right. Everything has got to be very well controlled, and you’re discussing with the students and postdocs. I had my own lab since I was twenty-nine, and then twelve, thirteen years later, I wanted to take stock of the big picture. Coming from Physics, you’re sort of trained as a physicist to try to think about the broader picture- the universal laws again. So I wanted to write a popular level book as a way of taking time out, to take stock of the big picture of how the immune system works.

DD There’s another reason that’s important to me. A lot of the greatest tragedies that have happened through history- I’m Jewish, so the Holocaust is one thing that comes to mind- come from a misunderstanding of the differences between people. One of the greatest themes that we get from studying the immune system is quite a deep understanding of what the differences between people really mean, and that was a really important story for me to tell. For example, if you asked people in the general public “what genes would you think might be different from one person to the next?” they’ll probably think of things like “the genes that control our hair color, our eye color, or our skin color” for example. In fact, the genes that vary the most from one person to the next are in our immune system. Not only are the genes that vary the most in our immune system, it’s actually crucial that they do vary, that they have that exceptional diversity. Because the way that we have evolved to survive disease requires this exceptional diversity in our immune system genes, or specifically, our MHC genes. So, in a way, it’s a really powerful celebration of human diversity, and I wanted to tell that story.

How did you keep a lab running during the writing of the book?

DD I took a year’s sabbatical leave. That basically meant I didn’t have to do my usual teaching and administrative duties. I still ran the lab. I still came in, did lab meetings. But I didn’t come in to the lab and do a lot of the stuff I would normally do, and I turned down a lot of invitations to conferences during that period of a year. We built a shed at the bottom of my garden and basically I sat in that shed for a year and wrote this book. I did also interview of course many of the scientists that were involved. I wanted to tell this sixty year long journey of the discovery of the MHC genes, and then how we learned all the things that they do in the human body. I interviewed a lot of the people that did the primary work, and if they were no longer with us, I also interviewed some members of their families just to get a sense of their state of mind, of how they did the work, and what they went through to win us that knowledge.

How did you find a publisher?

DD I didn’t have a good idea about that at the outset- I actually just thought, you know, I’ll write the book and it will be published somehow, just like I might do a paper and send it to J Exp Med. It took me a while to figure out how that worked. It turned out that it’s not so different from what we’re used to, in the sense that you essentially have to write a proposal, like I would normally have to write a grant proposal to do the research. That basically means an outline, a description of what would be in each chapter, and then some stuff about why the book is going to be important, who’s going to read the book, why I’m the right person to write the book- or at least I’m a person who could write that book. You have to certainly sell it a bit, to send that proposal to literary agents. There’s just a lot of guidance out there on the web about how to find an appropriate literary agent. Or you could just look in any other popular science book and see who their literary agent is, and send it to them. By chance, my proposal ended up with a literary agent in London whose other client was J.K. Rowling, of the Harry Potter books, so that seemed like it would be a great literary agent to be associated with**.

What is your lab currently working on?

DD What we’re working on now is using super-resolution microscopes to look at what happens at the immune cell surface when immune cells are switched on or off. The thing I love about microscopy is, as well as using it to answer specific questions, you know, to work out the details of some mechanisms by which some process works- the wonderful thing about microscopy is you might discover unexpected new phenomena. It’s a great tool for explorative science. That’s what led me to initially co-discover the immune synapse and membrane nanotubes. Now we’re using these newer microscopes that work at even higher resolution and we’re seeing that the same kind of cell can have subtle changes to the organization of its proteins at the cell surface which correlate with different states of health and disease. I’m now also much more connected to pharmaceutical companies. I’ve recently moved from Imperial College in London to Manchester and one of the things about that move is that I’m Director of Research for a center that’s connected to pharmaceutical companies. I’m trying to find out really what might be druggable in the way cell surfaces are organized, and how that may be used to impact the outcome of immune cell recognition.

* Some of their work on HLA and NK cells was published in JEM.

** Dan’s agent is Caroline Hardman.

The Viral Shake

A kerfuffle over whether or not the University of California at Berkeley was a place for serious scientists led directly to the creation of our sibiling publication, The Journal of General Physiology. Dr Flexner’s old Professor, Jacques Loeb, was banned from the pages of The American Journal of Physiology when he moved from the University of Chicago to the West Coast in 1902 (and thus “no longer represented a ‘major’ institution”). Eight years later, Flexner recruited Loeb to the Rockefeller Institute, and eight years after that, in 1918, Loeb launched The Journal of General Physiology.

So it’s numerologically appropriate that eight years after Avery and colleagues demonstrated in JEM that DNA was the “transforming principle”, Alfred Hershey and Martha Chase should publish their own work on the chemical nature of the hereditary material of viruses in JGP. These are the beloved Waring Blendor (sic) experiments*- Hershey had found the setting where phage** (and phage “ghosts”, i.e. protein shells) clinging to the bacteria would be spun-off without bursting the bacteria themselves.

T2 phage

T2 phage (illustration by Madalena Parreira).

The key to understanding Hershey and Chase’s experimental setup is quite simple: proteins contain sulfur & DNA doesn’t; the reverse is true of phosphorous. Growing phage in the presence of radioactive sulfur-35 or phosphorus-32 isotopes allows tracking of the different compounds’ fate simply by measuring radiation in bacterial cultures. By shaking the bacteria in the blender (or blendor), and then spinning the whole mix in a centrifuge, Hershey and Chase could use a Geiger counter to find which viral molecules were passed on the next generations (via synthesis in the bacteria). They conclude that:

“The experiments reported in this paper show that one of the first steps in the growth of T2 is the release from its protein coat of the nucleic acid of the virus particle, after which the bulk of the sulfur-containing protein has no further function.”

or, in other words

“We have concluded above that the bulk of the sulfur-containing protein of the resting phage particle takes no part in the multiplication of phage, and in fact does not enter the cell. It follows that little or no sulfur should be transferred from parental phage to progeny.”

IMG_0303

Hershey and Chase, JGP 1952, figure 1.

Though Hershey & Chase’s work is often referred to as “definitive” confirmation of the Avery group’s work, it is worth noting that the levels of contamination in their work vastly exceed those published in 1944- a fact the authors do not attempt to conceal:

“The radiochemical purity of the preparations is somewhat uncertain, owing to the possible presence of inactive phage particles and empty phage membranes.”

“The following experiments show that this is readily accomplished by strong shearing forces applied to suspensions of infected cells, and further that infected cells from which 80 per cent of the sulfur of the parent virus has been removed remain capable of yielding phage progeny.”

Even the best-case scenario

“The experiments described below show that this expectation is correct, and that the maximal transfer is of the order 1 per cent”

was unimaginable in Avery’s meticulous, painstaking biochemical work, and contamination had led Hershey to the wrong conclusion only a year before:

“The properties described explain a mistaken preliminary report (Hershey et al., 1951) of the transfer of S 35 from parental to progeny phage.”

Perhaps the most salient aspect of Hershey and Chase’s landmark study, what immediately stands out when reading the original manuscript and the rationale behind the experimental design, is that these experiments were not set up to test if DNA was the genetic material at all. They were optimized to examine if protein could be. But the idea of DNA as the genetic material was much more acceptable in 1952, and the use of radioactive isotopes labeling was very appealing in the heyday of the Atomic Age. So for many scientists at the time, Hershey and Chase’s 1952 JGP classic marked the definitive acceptance of deoxyribonucleic acid as the chemical agent of heredity.

* Matthew Cobb kills this romantic image: “This apparatus is often called a kitchen blender, which conjures up some kind of retro 1950s domestic device, all chrome and glass. Sadly this was not the case (…) the apparatus used by Hershey and Chase was a highly specialized, unstylish bronze-coloured piece of laboratory equipment’”. Dr Cobb may or may not be available to come to your kid’s party and tell him there is no Santa.

** A group of viruses that infect bacteria (short for bacteriophage).

Andersen, O.S. A Brief History of The Journal of General Physiology. 2005. 125:3.

Hershey, A.D., and Chase, M. Independent functions of viral protein and nucleic acid in growth of bacteriophage. Journal of General Physiology. 1952. 36:39-56.