Gregor Mendel Freidrich Miescher Frederick Griffith

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With recent advances in genetic technology enabling us to screen the whole genome of an organism, it’s hard to imagine a time when scientists didn’t even know that nucleotides existed.

National DNA Day honors the completion of the Human Genome Project in April 2003 and the discovery of the double helix of DNA in 1953. In this infographic we rewind time to explore the history of DNA and some of the landmark discoveries in the field of genomics.

1857

1869 GREGOR MENDEL The “Father” of genetics FREIDRICH Gregor Mendel became the “father” of genetics quite unintentionally through his work on hybrid pea plants. By breeding pea plants and observing patterns of traits, he MIESCHER established the principles of inheritance, After qualifying as a physician, Miescher observing that some traits in the pea plants moved to Tübingen to work in biochemist were dominant and some were recessive. Hoppe-Selver’s lab – his aim being to Using a paintbrush to transfer pollen from discover the building blocks of life. He one plant to another to create hybrids, was allocated the task of deciphering Mendel worked on his project for eight the composition of lymphoid cells (white years, creating thousands of pea plant blood cells). These cells were found hybrids and studying them meticulously. in great quantities in the pus from His work was published as Versuche über infections, and so Miescher tactically Pflanzen-Hybriden, meaning Experiments obtained old bandages from a clinic on Plant Hybridization in 1866. Whilst the and extracted the pus. He isolated an thoroughness of Mendel’s research was undiscovered molecule, nuclein, from appreciated in the field, the significance the cell nucleus, that was composed of what he had found went unnoticed.1 of hydrogen, oxygen, nitrogen and phosphorous. Advancing his work, Miescher later used salmon sperm to obtain nuclein. He believed that nuclein contained the molecules of heredity, and 1905 although he died in 1895, his work paved the way for the subsequent biological discoveries that followed.

1928 WILLIAM BATESON The “Rediscoverer of Mendel” FREDERICK Bateson was a biologist who, between 1900 and 1910, directed a “school” of genetics at the University of Cambridge. GRIFFITH He acknowledged the significance of Gregor Mendel’s findings and intended to pursue his work. The school consisted Discovering mainly of women, including his wife, her transformation sister and Mureil Wheldale. The group “ ” carried out breeding experiments in Griffith was a bacteriologist who studied the various plant and animal species that epidemiology and pathology of bacterial supported and enhanced Mendel’s laws pneumonia. In 1928, Griffith was studying of heredity. A letter in 1905 from Bateson two strains of Streptococcus pneumoniae that to a zoologist at Cambridge is the first were extremely different in their appearance documented use of the term “genetics”, and their ability to cause disease. The virulent from the Greek gennō , γεννώ , “to give S strain had a smooth capsule, while the birth”. Bateson also devised the word non-virulent R strain had a rough exterior “allelomorph”, which would later be and lacked a capsule. Griffith injected mice shortened to allele.3 with the S strain and they died, whereas mice injected with the R strain survived. Next, he chose to heat the virulent strain to kill it and then injected it into the mouse. As predicted, 1929 the mouse survived. Griffith then heated the non-virulent R strain and injected this alongside the virulent pneumonia that had been heated and killed, into the mouse. The mouse died. The scientist suspected that the killed virulent bacteria had passed on a trait to the non-virulent R strain that rendered it virulent. He believed that this trait or characteristic was the inheritance molecule, and that the process of passing this molecule 4 PHOEBUS on was “transformation”. LEVINE 1951 Levine was a biochemist at the Rockefeller Institute of Medical Research. He identified that DNA consists of nucleic acids: adenine (A), ROSALIND cytosine (C), guanine (G) and thymine (T), which are linked together through FRANKLIN, phosphate groups – the “backbone” of the molecule. Whilst some of his conclusions about the structure of JAMES WATSON DNA were incorrect (Levine believed there were only four nucleotides per & FRANCIS CRICK molecule of DNA), his work was key for later research that determined A chemist and X-ray crystallographer, DNA’s structure.5 Franklin joined King’s College London in 1951, where Maurice Wilkins was using X-ray crystallography to try to deduce the structure of DNA. Working alongside her student, Raymond 1961 Gosling, Franklin obtained high- resolution images of crystallized DNA fibers – nicknamed “Photo 51”. Using the image, Franklin was able to deduce that DNA forms a helical structure. What happened next proved to be one of the greatest injustices of all time in the scientific field. Franklin presented her findings at a King’s College lecture at which Crick and Watson were in attendance. Wilkins showed Crick and MARSHALL Watson the X-ray image of DNA that Franklin had obtained. The image confirmed the 3D structure that both NIRENBERG scientists had postulated for DNA. Using Photo 51 in addition to other resources, Crick and Watson developed the & HEINRICH chemical model of the DNA molecule. Franklin went to the Birbeck lab to work on the structure of tobacco mosaic MATTHAEI viruses, before tragically passing away Nirenburg, a biological chemist, in 1958. In 1962, the Nobel Prize in wanted to determine whether Physiology and Medicine was awarded DNA or RNA was the template for to Watson, Crick and Wilkins for solving protein synthesis. Working alongside the mystery of the structure of DNA. Matthaei, a postdoctoral fellow, he As the Nobel committee do not award started studying both molecules. posthumous prizes, Franklin was not awarded for her contribution In studying Escherichia coli, the 6 researchers found that uracil served to this work. as a messenger directing protein synthesis, meaning that it was RNA that transcribed genetic information from DNA. They discovered that 1999 the coding units for amino acids contained three nucleotides, i.e. a triplet. By combining four nucleotides into three letter codes there were 64 possible combinations, enough to encode the 20 amino acids. By 1966, Nirenberg had deciphered the 64 RNA three-letter codes for all 20 amino acids - the “language” of DNA – earning him a Nobel prize in 1968.7 SANGER

2000 RESEARCHERS SEQUENCE CHROMOSOME 22 As part of the Human Genome Project (HGP), using what were then regarded as novel gene sequencing technologies, researchers at the Sanger Institute in Cambridge sequenced the first ever FRUIT FLY human chromosome – number 22. Speaking of the discovery, Dr Francis Collin, then director of the National GENOME IS Human Genome Research Institute, said “To see the entire sequence of a DECODED human chromosome for the first time is like seeing an ocean liner emerge In March 2000, a team of out of the fog, when all you’ve ever researchers decoded the entire seen before were rowboats.” Due to genome of the Drosophila its small size and its associated role in melanogaster fruit fly. For several diseases, coupled with previous nearly 50 years prior, the fruit work from the early ‘90s, the scientists fly had been at the heart of opted to focus on chromosome 22. research investigating the They found that at least 545 genes role of genes in disease, and resided on this chromosome, allowing so this was a major triumph. geneticists to predict that the total The scientists discovered that number of genes on all human each fruit fly cell contains chromosomes would be in the approximately 13,601 genes, region of 80,000.8 making it the most complex organism to have its genome decoded at that time. This would prove to be a major stepping stone for the HGP.9 2003

2008

THE HUMAN GENOME PROJECT THE 1000 IS COMPLETE GENOMES In April 2003, the HGP was completed. An international effort PROJECT IS coordinated by the National Institute of Health (NIH), the HGP involved sequencing and mapping the LAUNCHED entirety of the genetic make up of Launched in 2008 and completed in 2015, our species, the Homo sapien. The the 1000 Genomes Project created the HGP provided scientists with the largest catalogue of human variation and ability to understand the blueprint genotype data available to the public. of what makes a human being, The project utilized the developments in and by doing so provided great sequencing technology and was the first of insight into why certain diseases its kind to sequence the genomes of a large occur, and how our genetics interact number of people. The goal was to identify with our environment to create our genetic variants with frequencies of at least phenotypes. The HGP was a complex 1 percent in the populations chosen for task only made possibly by the major the study, with the final data set published advances seen in genetic technologies containing data for 2,504 individuals from in the years prior to its completion. 26 populations. When the project ended, the When discussing the size of the European Molecular Biology Laboratory- genome, the NIH emphasized that if European Bioinformatics Institute (EMBL- each letter abbreviating each base of EBI) received funding from the Wellcome the human genome were printed in Trust to maintain the resource and expand standard print on A4 paper, it further. To achieve this, the International there would be a tower of paper Genome Sample Resource (IGSR) was reaching the heights of the established, and has the following aims: Washington Monument.10 Ensure the future access to and usability of the 1000 Genomes reference data. Incorporate additional 2012 published genomic data on the 1000 Genomes samples. Expand the data collection to include new populations not represented in the 1000 Genomes Project.11

THE “CRISPR REVOLUTION” BEGINS In 2012, a discovery was made in the labs of Jennifer Doudna and Emmanuelle Charpentier that would change the field of genomics forever – the potential of the CRISPR-Cas9 system for targeted gene editing was realized. CRISPR, standing for Clustered Regularly Interspaced Short Palindromic Repeats, is a bacterial defence system consisting of two key molecules: the Cas9 enzyme, and a piece of RNA known as the guide RNA. The enzyme functions as a pair of “molecular scissors” and can cut DNA strands at specific locations in the genome, allowing for sections of DNA to be added or removed. The guide RNA is a section of pre-designed RNA, typically 20 bases long, contained in an RNA scaffold. The scaffold can bind to DNA, and the pre-designed RNA acts as a cellular tour guide by guiding Cas9 to a targeted section of the genome. The guide RNA has bases that are complimentary to those of the target DNA sequence in the genome, ensuring that the guide RNA only binds to the target DNA sequence. Cas9 follows the guide RNA to the target sequence and makes a cut across both strands of the DNA. Recognizing a cut has been made, the cell tries to repair the strands. This process of repair allows scientists to introduce changes to the genes in the genome of a cell.12 Doudna and Charpentier’s discovery created immense possibilities and changed the field of genomics forever; once simply viewed as the fundamental building blocks of life, DNA now represents so much more. Research laboratories across the globe are conducting CRISPR research with a variety of possible applications, such as the editing of crops in agrigenomics, to the editing of genes in human disease. As the method of CRISPR-based gene editing is continuously refined, scientists progress one step closer to introducing gene editing into humans. What would Mendel think about that…?

REFERENCES

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2. Dahm, R. (2005). Friedrich Miescher and the discovery of DNA. Developmental Biology, 278(2), pp.274-288.

3. Keynes, M. and Cox, T. (2008). William Bateson, the rediscoverer of Mendel. Journal of the Royal Society of Medicine, 101(3), pp.104-104.

4. Nature.com. (2019). Isolating Hereditary Material: Frederick Griffith, Oswald Avery, Alfred Hershey, and Martha Chase | Learn Science at Scitable. [online] Available at: https://www.nature.com/scitable/nated/article?action=showContentInPopup&contentPK=336 [Accessed 5 Apr. 2019].

5. Hargittai, I. (2009). The tetranucleotide hypothesis: a centennial. Structural Chemistry, 20(5), pp.753-756.

6. Kcl.ac.uk. (2019). A photo that changed the world | King’s College London. [online] Available at: https://www.kcl.ac.uk/study/kings-in-time/a- photo-that-changed-the-world [Accessed 5 Apr. 2019].

7. NobelPrize.org. (2019). The Nobel Prize in Physiology or Medicine 1968. [online] Available at: https://www.nobelprize.org/prizes/medicine/1968/ nirenberg/biographical/ [Accessed 5 Apr. 2019].

8. Mayor, S. (2019). First human chromosome is sequenced. [online] PubMed Central (PMC). Available at: https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC1117192/ [Accessed 5 Apr. 2019].

9. Stephenson, J. (2000). Lords of the Fly DecodeDrosophilaGenome. JAMA, 283(12), p.1554.

10. National Human Genome Research Institute (NHGRI). (2019). All About The Human Genome Project (HGP). [online] Available at: https://www. genome.gov/10001772/ [Accessed 5 Apr. 2019].

11. Internationalgenome.org. (2019). About | 1000 Genomes. [online] Available at: http://www.internationalgenome.org/about [Accessed 5 Apr. 2019].

12. Biolabs, N. (2019). CRISPR/Cas9 & Targeted Genome Editing: New Era in Molecular Biology | NEB. [online] Neb.com. Available at: https://www. neb.com/tools-and-resources/feature-articles/crispr-cas9-and-targeted-genome-editing-a-new-era-in-molecular-biology [Accessed 5 Apr. 2019].