The discovery of the molecule of heredity: Matthew’s new Guardian piece

This is another anniversary in the history of genetics: it’s been seventy years since three investigators at Rockefeller Institute in New York City (now Rockefeller University, where I began grad school)—Oswald Avery, Colin MacLeod, and Maclyn McCarty (“AMM”)—discovered that DNA was the genetic material. Although their paper on this work was published in 1944 (reference and link below, full pdf here), May 26, 1943 was the day that Oswald Avery wrote to his brother announcing the discovery. (You can see Avery’s scrawled letter here.)

This finding truly was the beginning of the frenzy in molecular genetics that led directly to the discovery of the structure of DNA by Watson and Crick, and then to elucidating how DNA produced proteins.  For it wasn’t until we knew what the genetic material actually was that we could determine its structure.  And before the AMM paper, nobody knew for sure.

I’ve read the paper several times, and it’s a masterpiece of meticulous work and scientific exposition. What it showed was that one could change the hereditary nature of pneumonia-causing bacteria (that is, whether they could be virulent) by “transforming” nonvirulent strains with DNA.  These strains had been killed, but could be revitalized (and made virulent) by replacing their DNA with that from nonvirulent cells. The virulence persisted (i.e., was inherited) after transformation. This transformation was not effected by protein, so that ruled out proteins as the genetic material. The way that AMM did this in those early days of molecular biology was masterful.

But I’ll let Matthew tell you about it in his new article in the Guardian, “Oswald T. Avery, the unsung hero of genetic science.”  Avery had two collaborators on this, Colin MacCleod and Maclyn McCarty, but Avery was the driving force behind the research.

Their discovery, which was soon replicated, certainly deserved a Nobel Prize, but none of the three men ever got it. I suppose that’s why Matthew calls Avery an “unsung hero.” If you’re not a biologist you probably won’t have heard of the three men and their paper. But those of us working in genetics all know the work simply as “Avery, MacCleod andMcCarty”, and it’s a good time for all of us to remember their contribution.  Go read Matthew’s article now: it’s very good and clearly explains what they did and why it was important.

This is what scientific history looks like: the title and summary of their paper. Note the “conclusion”.  You can read “hereditary material” for “fundamental unit of the transforming principle.

Picture 4

Picture 1Picture 2

One side note: the authors cite my academic grandfather, Theodosius Dobzhansky, for recognizing that the phenomenon of transformation itself gives a clue that the genetic material might be involved. I’m chuffed that support for DNA as the hereditary molecule came from an evolutionary geneticist:

Picture 1

Here’s the part of Avery’s 14-page letter where he says that, after “many heartaches and heartbreaks,” they figured out that the transforming principle seemed to be DNA. “Who could have guessed it?”, he adds. Picture 2

And here are the three unsung heroes:

427px-Oswald_T._Avery_portrait_1937

Oswald Avery

ColinMacCleod

Colin MacCleod

763px-Maclyn_McCarty_with_Francis_Crick_and_James_D_Watson_-_10.1371_journal.pbio.0030341.g001-O

Maclyn McCarty (l.) with J. D. Watson (middle) and Francis Crick (r.)Further

You can read more about this experiment at Wikipedia, which has a more detailed description, or in Horace Freeland Judson’s masterful account of the history of molecular genetics, The Eighth Day of Creation.

And isn’t it amazing that a primate could figure this out?

_________

Avery, Oswald T.; Colin M. MacLeod, Maclyn McCarty (1944). “Studies on the Chemical Nature of the Substance Inducing Transformation of Pneumococcal Types: Induction of Transformation by a Desoxyribonucleic Acid Fraction Isolated from Pneumococcus Type III”. Journal of Experimental Medicine 79 (2): 137–158. doi:10.1084/jem.79.2.137

17 Comments

  1. bonetired
    Posted June 3, 2013 at 6:11 am | Permalink

    When did it become “deoxyribonucleic” as opposed to “desoxyribonucleic”?

    • David Hillis
      Posted June 3, 2013 at 6:42 am | Permalink

      In the early days of molecular biology, two variants (deoxy…and desoxy) were often seen in the English literature. The deoxy- form is actually the preferred English spelling, although désoxy- is used in French and German. Appendix 9-1 of the Amemerican Chemical Society Style Guide says:

      “APPENDIX 9-1
      Recommended Spelling List
      Many words in regular usage, as well as many technical terms, have two or more
      acceptable spellings. The following list gives recommended spellings and capitalizations, where appropriate, for some terms not found in easily accessible dictionaries, words often misspelled, common expressions, and words for which the
      ACS preference may not match your dictionary’s.

      ….
      deamino (not desamino)
      deoxy (not desoxy)
      ….”

      It took a while for deoxy- to win out in the English literature, but it is now standard.

      • David Hillis
        Posted June 3, 2013 at 6:44 am | Permalink

        Ironic that I could not even spell “American”.

        • Torbjörn Larsson, OM
          Posted June 3, 2013 at 2:31 pm | Permalink

          Oh, it takes many small “me” to balance the large “US”.

  2. Posted June 3, 2013 at 7:15 am | Permalink

    Thanks goodness not only DNA can be transcribed, but also hand-written letters:

    http://profiles.nlm.nih.gov/ps/retrieve/ResourceMetadata/CCBDBF

    • Notagod
      Posted June 3, 2013 at 8:23 pm | Permalink

      Thanks! It seemed that the content of Avery’s letter to his brother would always be a mystery and now you have solved the code.

  3. Posted June 3, 2013 at 7:43 am | Permalink

    Good read. Thanks for writing it, Matthew.

    b&

  4. Jim Thomerson
    Posted June 3, 2013 at 7:52 am | Permalink

    Where does the tetranucleotide structural hypothesis fit into this story? As I understand it, this hypothetical structure was too simple to allow DNA to be the genetic material. I think it was based on observation of equal amounts of the four nucleotides in E. coli DNA, but am not sure of that. Chargraff’s work showing different percentages in other organisms was not immediately accepted.

  5. Edward Hessler
    Posted June 3, 2013 at 9:42 am | Permalink

    I’m so glad you posted this and also for the link to Dr. Cobb’s article. It has made me think about the history of science. I know very little about molecular biology but did know these names and their contribution. I’ve always been in awe of their cleverness and hard work (and then to have it fall flat or not be recognized. Scientists born at the wrong time and in the wrong place comes to mind.) It is only a dozen years later that Hershey and Chase did similar work on phage (or am I wrong) which was better received but I’m not sure it compares with the rigor of AMM. I’ve got to hie to the library and pick up a history of molecular genetics. I look forward in future to Dr. Cobb talking about this later work if time, willingness and the interests of this website permit. Thanks again.

  6. Gregory Kusnick
    Posted June 3, 2013 at 10:29 am | Permalink

    These strains had been killed, but could be revitalized (and made virulent) by replacing their DNA with that from nonvirulent cells.

    This seems somewhat garbled and makes it sound as if nonvirulent DNA has the power both to bring dead bacteria back to life and to confer virulence upon them.

    In fact (if I understand it right) it was the donor bacteria that were killed in order to extract their DNA, and those donor bacteria were of a virulent strain.

    • Thanny
      Posted June 3, 2013 at 11:05 am | Permalink

      What he said.

      The context makes it clear that the “non” in that sentence is a typo (thinko?).

    • jaxkayaker
      Posted June 3, 2013 at 12:01 pm | Permalink

      “…it was the donor bacteria that were killed in order to extract their DNA, and those donor bacteria were of a virulent strain.”

      Your understanding is correct. DNA from killed, virulent bacteria was absorbed by a live, nonvirulent strain and transformed it to a virulent form.

  7. jaxkayaker
    Posted June 3, 2013 at 12:02 pm | Permalink

    I wonder to what extent, if any, the Avery et al. results were downplayed because the researchers were M.D.s, not Ph.D.s.

  8. Ken Pidcock
    Posted June 3, 2013 at 5:32 pm | Permalink

    This finding truly was the beginning of the frenzy in molecular genetics that led directly to the discovery of the structure of DNA by Watson and Crick, and then to elucidating how DNA produced proteins.

    I’m not so sure of that. I think if you go through the papers of the phage group, you’ll be hard-pressed to find citation to Avery, MacLeod and McCarty. (Why would Hershey and Chase be considered revolutionary if we already knew?) This was medical bacteriology, and I wonder if physicists were paying attention. My sense is that AMM was folded into the story at a later date.

    • Posted June 3, 2013 at 10:24 pm | Permalink

      No, the phage group knew all about it. Delbrück saw the letter to Roy Avery (they were both at Vanderbilt) shortly after Roy received it in 1943. Luria discussed with Avery before publication. Hershey cited Avery’s work in 1946, they were all at the various meetings where Avery’s finding was discussed.

      The phage group just didn’t accept the implication of Avery’s work that all genes might be made of DNA, because they clung onto the DNA is boring line. Plus they were utterly blind to anything that didn’t come from their system.

      Amazingly, even in 1953, after the double helix, Hershey was still saying in public that he did not expect DNA to be the sole basis of heredity!

  9. madscientist
    Posted June 4, 2013 at 3:43 am | Permalink

    “And isn’t it amazing that a primate could figure this out?”

    Yes – and not so amazing that it wasn’t revealed by god to the sort of primate who wears funny robes and claims that god’s his good buddy.

  10. marksolock
    Posted June 9, 2013 at 7:45 am | Permalink

    Reblogged this on Mark Solock Blog.


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