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13:00in productionCh. 1 · A gene assumed to be continuous/ 13:00 · ceiling 15 min
Genetics · Life sciences

RNA splicing

In 1977 Phillip Sharp and Richard Roberts, examining adenovirus RNA under the electron microscope, found that genes are not continuous stretches of code but are broken up by non-coding introns removed during splicing.

Working independently in 1977, Phillip Sharp and Richard Roberts hybridised adenovirus RNA back onto its own DNA and saw loops of DNA with no matching RNA, evidence that the viral gene was interrupted by stretches of sequence absent from the finished messenger RNA. Extended to genes generally, the finding showed that protein-coding genes are split into exons, which end up in the mature RNA, and introns, which are cut out and discarded in a process called splicing. The discovery reshaped the basic model of what a gene is and shared the 1993 Nobel Prize in Physiology or Medicine between Sharp and Roberts.

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Chapters & takeaways6
  1. 0:08
    A gene assumed to be continuous

    Before 1977, the working assumption was that a gene's coding sequence ran uninterrupted, matching its finished messenger RNA base for base.

  2. 2:10
    Loops under the electron microscope

    Examining adenovirus RNA hybridised to its own DNA, Sharp's and Roberts's groups saw looped-out sections of DNA with no corresponding RNA.

  3. 4:20
    Naming exons and introns

    The looped-out DNA marked introns, sequence removed from the RNA, while the matched sections were named exons, the parts retained in the mature transcript.

  4. 6:30
    From one virus to genes generally

    The split-gene structure turned out not to be a quirk of the virus but a general feature of genes across complex organisms.

  5. 8:40
    One gene, many proteins

    Because exons can be joined in different combinations, alternative splicing lets a single gene produce more than one version of a protein.

  6. 10:50
    Why this discovery still matters

    Worth an hour because it overturned a basic assumption about what a gene is, one that genetics had simply taken for granted before 1977.

Worth your time?

Yes. Study the whole thing.

4.5/ 5
What works
  • the directness of the electron-microscope image, an actual loop of unmatched DNA, as evidence for something as abstract as gene structure
  • the way one virus experiment turned into a rule about genes in general
  • the clean link from split genes to the practical payoff of alternative splicing
What does not
  • it does not detail the molecular machinery, the spliceosome, that performs the cutting and rejoining
  • the account centres on one virus and a small number of labs, understating how many groups converged on the same finding in 1977
Study it if
  • readers who assume a gene is one continuous stretch of code
  • anyone curious how a single gene can make several different proteins
  • students meeting molecular genetics for the first time
Skip it if
  • readers looking for the full biochemistry of the spliceosome
  • anyone wanting a single simple mechanism rather than an added layer of gene structure
The written brief3 min read

A gene assumed to be continuous

Until 1977, the standard assumption in molecular biology was that a gene’s coding sequence ran as one continuous stretch, matching its messenger RNA base for base from start to finish. Phillip Sharp and Richard Roberts, working independently with the adenovirus, a virus that infects human cells, found evidence that this was not always true. Their laboratories examined how the virus’s RNA related to the DNA it had been copied from, and found sections of the viral DNA with no corresponding sequence in the finished messenger RNA at all. Rather than the gene and its RNA product matching exactly, the gene appeared to contain extra material that was present in the DNA but absent from the RNA that actually got used to make protein.

Loops under the electron microscope

The key evidence came from hybridising adenovirus messenger RNA back onto the single-stranded DNA it had originally been transcribed from, then examining the resulting molecule under an electron microscope. Where RNA and DNA matched, the two strands paired up into a straight double-stranded segment; where the DNA contained sequence absent from the RNA, that DNA looped out on its own, unpaired, forming a visible bulge in the image. Susan Berget, a postdoctoral researcher in Sharp’s laboratory, was central to producing this evidence, and the pattern of loops showed unambiguously that a single gene’s DNA was broken into multiple separated stretches, with sequence removed before the RNA reached its final, functional form.

Naming exons and introns

The finding held up completely and was quickly generalised beyond the one virus: genes across complex organisms, not only adenovirus, turned out to be built from coding regions, later named exons because they are expressed in the mature RNA, interrupted by non-coding regions, named introns, which are transcribed but then cut out during a process called RNA splicing. Other groups working around the same time, including Louise Chow and Thomas Broker, reached compatible conclusions independently, reinforcing that this was a real and widespread feature of gene structure rather than an artefact of one experiment. Sharp and Roberts shared the 1993 Nobel Prize in Physiology or Medicine for the discovery.

From one virus to genes generally

What the original electron-microscope experiments did not resolve was the molecular machinery responsible for the removal itself: identifying the spliceosome, the complex of small nuclear ribonucleoprotein particles that recognises intron boundaries and carries out the cutting and rejoining chemistry, took further research beyond the initial imaging work. The 1977 studies also focused on a specific viral system, so while the general conclusion, that genes can be interrupted, proved to be broadly true, the details of how frequently and how variably splicing occurs across different genes and species had to be established gene by gene in the years that followed.

One gene, many proteins

Splitting genes into exons and introns turned out to have a major practical consequence: because a cell can choose to join different combinations of exons together when producing mature RNA, a single gene can be spliced in more than one way to produce more than one version of a protein, a process called alternative splicing that affects the great majority of genes with more than one exon in complex organisms. This gave cells a way to expand the range of proteins they can make without needing a separate gene for every variant, and it reshaped how biologists think about the relationship between the size of a genome and the complexity of the organism it builds.

Why this discovery still matters

This is worth understanding because it is a case of a basic assumption, that a gene is one uninterrupted stretch of code, being overturned by a single clear image rather than by years of accumulating doubt. The loop in the electron micrograph is about as direct as evidence gets: either the DNA matches the RNA everywhere, or it visibly does not. Following the discovery through to alternative splicing also shows how a structural finding about gene anatomy turned into an explanation for something as consequential as how a limited number of genes can build a much larger number of proteins.

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