Monday, October 28, 2013

Gender Bias in Science, Part IV: Martha Chase

Martha Chase in 1953
Many readers who have taken a high school- or college-level biology class in the past 50 years have likely heard of the "Hershey-Chase" experiment, performed in 1952.  Sometimes its called "Hershey & Chase" or even sometimes just "the blender experiment."  You might not remember it, but you probably learned about it at one time or another if you took some kind of biology course.  It's that important and that famous.   

The subject of today's post is the Dr. Martha Chase of "Hershey-Chase" fame.  Her name will be forever associated with what is considered to be the definitive experiment showing that DNA, not protein, is the inheritable genetic material.  Let's rephrase that, because it is an important discovery that we take for granted today: Hershey and Chase showed that genes are made of DNA, not protein.  As you can imagine, that was a big deal.  Before that, many scientists thought that DNA was frankly not very important and pretty uninteresting.  Many thought that genes were instead made out of protein.  Hershey and Chase forever changed that with a simple series of experiments.    

We'll get into the historical background of the experiments in a moment.  If you've read some of the previous posts in this series, you can probably guess that the reason we're talking about Chase is that, despite this impressive experiment that bears her name, Martha Chase watched Alfred Hershey receive a Nobel Prize in 1969 for the discovery, while she sat on the sidelines.

Was this an example of gender bias, or simply a case of giving credit to the more deserving half of the pair?  Let's talk about the facts of the case.  We'll go through the Hershey-Chase experiment and the somewhat tragic life of a legendary geneticist after the jump.        
  
I want to first mention that one fact that sets Chase apart from some of the previous women we discussed in our series is that Martha Chase's career was cut short by personal set-backs and tragedy.  Chase helped to design one of the most elegant experiments in the early history of molecular biology.  Hershey and Chase set off the race to discover the structure of DNA.  However, that wasn't enough to prevent her scientific career from fizzling out.  In contrast, Lise Meitner, Jocelyn Bell Burnell, and Chien-Shiung Wu all had impressive scientific careers and received many honors despite losing out on the Nobel.  Martha Chase's story is a little more tragic.  It's also very hard to find much information about her life compared with the other women we've already discussed on this blog.  Martha Chase is more of an enigma.     

Phages infecting a bacteria cell
Chase was born in the Cleveland Heights neighborhood of Cleveland, Ohio in 1927.  She grew up with science: her father was a medical school professor at Case Western Reserve University.  She even performed her first genetic experiments on fruit flies while still an undergrad at the College of Wooster.  She received her bachelor's degree from the College of Wooster in 1950 and her PhD from the University of Southern California in 1964.     

The actual Hershey-Chase experiment was conducted in 1952, between her time in Wooster and California.  She started working as a research technician in the lab of Dr. Alfred Hershey at Cold Spring Harbor Laboratory on Long Island, NY in 1950 at the age of 21.  Hershey and many other prominent researchers at Cold Spring Harbor were working on bacteriophages (or just phages, for short), which are viruses that can infect bacteria (discussed in a previous blog post).  These researchers, including Salvador Luria and Max Delbruck, who we will mention a bit later, became known as "The Phage Group."  The work they did with phages helped to identify many of the basic principles of cell and molecular biology.      

Because phages infect bacteria and turn them into "factories" for producing more phages (just like viruses that infect your cells use them to make more virus), researchers knew that bacteriophages transmitted some sort of genetic information (ie, the "blueprints" for new phages) to the bacteria when they infected them.  Scientists at this time were thus trying to understand genetic inheritance by studying phages and how they transmit this genetic information to their bacteria hosts.  From electron micrographs like the one shown above, scientists also knew that phages did not completely enter the bacterial cell.  It was hypothesized that they injected something into the bacteria cell, using their tale almost like a hypodermic needle.  If only the researchers could figure out what it was that they injected, they knew that there must be some genetic material in there.

Bacteriophage anatomy
It was known at this time that bacteriophages consist of two types of molecules: protein, which makes up the head (or capsid) and tail of the phage, and DNA, which is encapsulated by the head.  A major question in biology in the first half of the 20th century was whether DNA or protein was the genetic material.  Scientists knew about genetic inheritance, but they did not yet know exactly what the chemical composition of a gene was.  Figuring that out would help understand the molecular basis of genetic transmission.  Was it DNA or protein?  This was the question that Hershey and Chase tried to address in their famous experiment.

Many biologists in the first half of the 20th century believed that the genetic material of cells had to be protein.  This idea partly dated back to a scientist named Phoebus Levene.  Pheobus Levene made several great contributions to biochemistry; he discovered both ribose sugar (the 5-carbon sugar component of RNA) and deoxyribose sugar (the 5-carbon sugar component of DNA).  However, in 1910, Levene proposed an incorrect structure for DNA (called the tetranucleotide structure) that made the molecule seem too simple to be able to carry any sort of complex information with in it. 

Phoebus Levene
Later on, however experiments by Oswald Avery, Colin MacLeod, and Maclyn McCarty, published in 1944, strongly suggested that DNA was the material of genetic inheritance.  However, definitive enough proof was still lacking, and the idea was not completely accepted.  Biologists were still hesitant to abandon the idea that genes were made from protein.  More  support for DNA's role as the genetic material came from Edwin Chargaff, who found that DNA composition varied by species.  Still, many geneticists continued to believe that DNA was too simple a molecule to carry enough genetic information to create an organism; many felt that the genetic material had to be protein.  It wasn't until 1952 that Hershey and Chase delivered what is now considered to be the defining experiment that demonstrated the role of DNA in inheritance. 

Hershey and Chase took advantage of the fact that protein and DNA have different chemical compositions.  While the structure of DNA was not known exactly, it was still known that DNA contains phosphorus (P) atoms but no sulfer (S) atoms.  Protein, on the other hand, contains sulfur (S) atoms within in the amino acids methionine and cysteine (amino acids are the building blocks of proteins).  Protein does not contain phosphorous except under certain circumstances when certain enzymes (called kinases) add phosphate groups (which contain P atoms) onto certain proteins.  This process is called phosphorylation.  But, even then, the P content of proteins is much lower than the P content of DNA.  For the purposes of this post, you can consider proteins to be phosphorous (P)-free and consider DNA to be sulfur (S)-free.    

The Hershey-Chase Waring Blender
Phosphorous and sulfur both have non-radioactive and radioactive atomic forms, called isotopes.  The P-32 isotope of phosphorous and the S-35 isotope of sulfur are both radioactive.  By taking T2 bacteriophages (a well characterized and studied phage species at the time) and allowing them to replicate in the presence of E. coli bacteria and S-35 or P-32, they generated bacteriophages that had either radio-labeled protein (labeled with S-35) or radio-labeled DNA (labeled with P-32).

They then took the protein-labeled or DNA-labeled phages and infected more E. coli bacteria.  They then put the bacteria/phage mix into a Warring blender to sheer-off the parts of the phages that remained stuck on the outside of the bacteria.  The did this carefully so as not to disrupt the bacteria themselves; they tried other methods before using the blender, at the suggestion of a fellow genetics researcher, Margaret McDonald.  The Warring blender they used, a not-very-elegant steel model, will forever be famously known as an intricate component of the experiment.

After blending their bacterial/phage cultures, Hershey and Chase could then separate out the bacteria from the phages and left over phage parts in a centrifuge.  A centrifuge spins a sample to separate things based on a combination of size and density; when Hershey and Chase centrifuged their test tubes containing bacteria and phages, the bigger, heavier bacteria sank to the bottom of the tube (in what is called the pellet) while the phages remained at the top (in what is called the supernatant).  This allowed them to separate out the bacteria and phages and look at how much radioactivity transferred from the original radioactive phages to the bacterial cells.     

What they found was that the phages that had radio-labeled (P-32-labeled) DNA had passed this  radioactivity on to the bacterial cells, while the phages that had radio-labeled (S-35 labeled) protein did not made the bacterial cells radioactive.  Almost 80% of the radioactive DNA was transferred from the bacteriophages to the cells; almost none of the radioactive protein transferred to the cells.     

The Hershey-Chase Experiments, in a nutshell
These results showed that, during infection, the phages were transmitting their DNA, but not their protein, to the bacterial cells that they were infecting.  This experiment provided the evidence  that DNA, not protein, is the hereditary material.

Now, it is important to note that Hershey himself originally believed that genes must be made of protein; Hershey initially wanted to disprove the original experiments of Avery, MacLeod, and McCarty.  However, when Hershey and Chase rechecked their data and repeated their experiments, they found that the results were clear, repeatable, and irrefutable.  In science, you have to be willing to sometimes admit to yourself that your ideas are wrong.  But, likewise, a fun part of science is being able to form new ideas based on new facts at hand.  Hershey was converted to the DNA camp.      

While the experiment and its results were fairly simple, the impact was enormous.  This intensified the race to determine the molecular structure of DNA.  James Watson, co-discoverer of the DNA double helix, wrote:

Martha Chase and Alfred Hershey, 1953
The Hershey-Chase experiment had a much broader impact than most confirmatory announcements and made me ever more certain that finding the three-dimensional structure of DNA was biology's next important objective.  The finding of the double helix by Francis Crick and me came only 11 months after my receipt of a long Hershey letter describing his blender experiment results.

Interestingly, Watson's near-immediate appreciation of the Hershey-Chase experiment was not widespread.  In his book, The Double Helix, Watson wrote about his experience reading parts of Hershey's recent letter to him at a conference he attended.  He wrote that  "...almost no one in the audience of over 400 microbiologists seemed interested as I read long sections of the letter."  

Watson and Crick's DNA model
Nonetheless, it is good that Watson saw the importance of the Hershey-Chase experiment when many of his peers did not, as he and his colleague, Francis Crick, were spurred on to discover the molecular structure of DNA and figure out the very mechanism of genetic inheritance itself.  The Francis and Crick model was published it in the journal Nature only 11 months after they learned of the Hershey-Chase experiment.     

Unfortunately for Martha Chase, though, the Hershey-Chase experiment marked the pinnacle of her scientific career; it was all downhill from there.  Not long afterward in 1953, she left Cold Spring Harbor, though she frequently visited for summer meetings of the Phage Group.  After leaving Hershey's lab, she worked briefly at Oak Ridge National Laboratory and at the University of Rochester.  Then, in 1959, she went to the University of Southern California to study and perform research for her PhD, which she was awarded in 1964.

After receiving her PhD, however, Chase's scientific career seems to have fizzled out.  As you may guess, being a woman didn't exactly help her in gaining the credit she deserved from her time at Cold Spring Harbor.  She worked in laboratory jobs at USC for a while, but a combination of illness and being laid off from her research job in the late 1960s led to her moving back to Cleveland Heights and living with her father, Samuel Chase.

While at graduate school in the late 1950s, she had married a fellow scientist whom she had met in California, Richard Epstein, but they divorced after less than a year of marriage.  According to a friend and colleague, Walter Szybalski, her divorce "left a deep scar."   She never remarried and never had any children.  Her divorce, coupled with her scientific career difficulties, apparently led to heavy drinking and smoking that helped create some health problems.  Martha Chase died of pneumonia on August 8th, 2003.  She was 75, and living in Lorain, Ohio, a Cleveland suburb.  For decades before her death, she suffered from a form of dementia that robbed her of her short-term memory.  She found joy in the simplicity of knitting.  She was survived only by a younger sister.  It is difficult to find much more detailed information about Martha's later life beyond that.   

Luria and Delbruck at Cold Spring Harbor, 1953
Despite the impressive experiment that bears her name, Martha Chase had to watch the 1969 Nobel Prize go to Alfred Hershey and 2 other male colleagues, Salvador Luria and Max Delbruck, for their contributions to the "genetic structure of viruses."

Please note that I'm not trying to vilify Luria and Delbruck at all.  They deserved a Nobel prize wholeheartedly.  Their famous Luria-Delbruck experiment in 1943 demonstrated that genetic mutations in bacteria arise randomly in the absence of selection, not as a consequence of selection; thus, they showed that Darwin's theory evolution by which natural selection acts on random mutations is applicable to both complex organisms (like us) as well as single-celled organisms like bacteria.  Their contributions were important and deserving.  Hopefully I can discuss the Luria-Delbruck experiment in a future post.       

However, the fact that Luria and Delbruck deserved a Nobel prize does not take away from the simple fact that Alfred Hershey received a Nobel Prize while Martha Chase did not.  Like all of the other women in our series, we can't know with certainty how much a role her gender played in this decision, but it is hard to imagine that gender did not play some role.  It is very likely that, because she was a research technician, she was viewed as simple a "set of hands" with which Hershey performed his experiments.  We'll never know exactly how much her gender played in strengthening  that viewpoint, but it is very likely that the fact that she was a woman made some believe that she had little intellectual input into the research.

Quite frankly, we don't have any evidence of what the relative intellectual contributions of Chase and Hershey actually were to the experiments, particularly since everyone involved is dead.  Unfortunately, no witnesses remain.  However, we already saw in the case of Chien-Shiung Wu that even a high-level, brilliant woman scientist could be viewed by the Nobel committee as merely "technical assistance" for the men running the show.      

It is particularly interesting to note that it was not common practice in the 1950s to list laboratory assistants as authors on research publications; the paper that Hershey and Chase published in the Journal of General Physiology to describe their famous experiment had both of their names listed as authors.  The fact that Hershey approved of putting Chase's name on this paper strongly hints that her role was more than just "technical assistance."  Hershey's other actions don't suggest that he was overly generous with credit.  In fact, Hershey himself provided perhaps the biggest insult to Martha Chase when giving his Nobel lecture, titled "Idiosyncracies of DNA Structure."  In this lecture, he never even bothered to mention Martha Chase's name once.

Still, the fact remains that hundreds of thousands of high school and college students read and learn about the Hershey-Chase experiment every year in biology classes around the world.  No one can ever take away that kind of recognition from Martha Chase; her name has reached a legendary status.  Unfortunately, though, not all students probably learn that Chase was a woman, and I'm sure that far fewer learn anything about her somewhat tragic story.
        
Even Chase's New York Times obituary had a diminishing air to it, describing her life by the simple headline, "Martha Chase, 75, Researcher Who Aided in DNA Experiment." The article even went so far as to refer to Chase and Hershey as "Ms. Chase" and "Dr. Hershey," despite the fact that both had PhDs.  Was that an example of the "Matilda Effect" or just a coincidental error?  We'll never really know for sure.             

Text and original color diagrams © 2013 TheMadScienceBlog; photographs are public domain.

Sources and Further Reading
  • S. Aldridge.  "The DNA Story."  Royal Society of Chemistry.  Available here.
  • O.T. Avery, C.M. MacLeod, M. McCarty.  "Studies on the Chemical Nature of the Substance Inducing Transformation of Pneumococcal Types."  Journal of Experimental Medicine.  1944.  79:137-159.  Available here
  • T.A. Brown.  Genomes. 2nd Edition.  Oxford: Wiley-Liss.  2002.  Ch. 1. "The Human Genome" [Available here] and Ch. 4. "Studying DNA" [Available here].   
  • E. Chargaff.  "Chemical Specificity of Nucleic Acids and the Mechanism of Their Enzymatic Degradation."  Experientia.  1950. 6:201-209.
  • Cold Spring Harbor Library.  "Coming of Phage."  Available here.  [Contains the picture of the Waring Blender]
  • K.E. Cullen.  "Chase, Martha (1927-2003). American Geneticist."  Encyclopedia of Life Sciences; Vol. 1.  2009.  Infobase Publishing p. 182.  
  • M. Dawson.  "Martha Chase Dies."  The Scientist.  20 August 2003.  Available here.  
  • A. Hershey and M. Chase.  "Independent Functions of Viral Protein and Nucleic Acid in Growth of Bacteriophage."  Journal of General Physiology.  1952.  36:39-56.   Available here or here.
  • S. Jaffe.  "Defining DNA as the Hereditary Molecule."  The Scientist.  24 Aptil 2004.  Available here.   
  • S. Lavietes.  "Martha Chase, 75, Researcher Who Aided in DNA Experiment."  New York Times.  Available here.
  • W. Szybalski.  Cold Spring Harbor Laboratory Oral Histories: "Walter Szybalski on Martha Chase." [Available here] and "Walter Szybalksi on The Hershey Chase Experiment." [Available here].  
  • J.D. Watson and F.H.C. Crick.  "A Structure for Deoxyribose Nucleic Acid."  Nature.  1953.  171:737-738.  Available here.





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