A tribute to Dick Cotton from Michael Watson. Part 2 of the inaugural Richard Cotton Memorial lecture.

1. Richard (Dick) GH Cotton
He May Have Been a Bit Before His
Time
Michael S. Watson
American College of Medical Genetics
and Genomics

2. Career with Threads to Major Healthcare Innovations
• A career that:
▫ focused on the prevention and treatment of genetic
disorders.
▫ impacted the development of many of the healthcare
programs most valued by the public today such as newborn
screening
▫ will impact the integration of genetics and genomics into
healthcare well into the future.
 mutation detection
 mutation databases
 world-wide partnerships

3. 1960s – PKU
• Dick began his career studying biochemical genetics in bacteria
and synthesis of amino acids
• This led to his developing a novel affinity adsorbent to
phenylalanine hydroxylase (1968) to aid in the study of
structure and function of the enzyme
▫ Doctoral thesis – “Studies on the enzymes concerned with
phenylalanine and tyrosine biosynthesis”
• He went on to do fundamental postdoc work on monoclonal
antibodies that led to a Nobel Prize for Physiology or Medicine
award to his mentor in 1984
▫ Today we have monoclonal antibody treatments such as
Rituximab

4. 1970 – 80s
• Returned to research in amino acids
▫ Generated sufficient protein sequence to allow Woo’s initial
cloning of phenylalanine hydroxylase (PAH)
• Appreciated the role of BH4 in PAH enzyme activity
▫ First DHPR deficient patient was found in Australia (1975)
 Developed first DHPR blood assays that became basis for
diagnosis at the gene product level
 Conceived the use of tetrahydrobiopterin (BH4) loading tests to
identify individuals with severe variants in PAH
▫ Led to Kuvan (BH4)as a PKU treatment for some patients

5. 1990s
• Founded journal Human Mutation in 1992 to catalog variation
and relationships to disease severity

6. Late 1990s -2000s
Frustrated by Difficulties in Studying PAH and DHPR
Genes
• Recognized that an underlying structural susceptibility of
mismatched DNA strands could be exploited by demonstrating
that they could be exposed by enzymatic or chemical cleavage
▫ Opened up the opportunity to detect every single base
variant in a gene
• Led to a career in mutation detection methods
• Led development of HUGO group on mutation detection
▫ Formed HUGO Database Initiative that ultimately became
the Human Genome Variation Society (HGVS)
• Led development by HGVS (2001) of standards for variant
nomenclature

7. Enzyme Cleavage Method for Mutation Detection

8. Inspired by “Completion” of Human Genome Project
• Recognized need for international effort to systematically:
▫ Collect
▫ Curate
▫ Interpret
▫ Share
information on genetic variation
•
• Led to the formation of HVP in Melbourne in 2006

9. Late 2000s -
• Encouraged and cajoled colleagues to adopt data collection
tools (LSDBs) and to share

10. • A remarkable career that ended before he could see the fruits
of his work in projects like Global Globin 2020 and the BRCA
Challenge
Cheers to Dick