Professional Documents
Culture Documents
d’éthique en désaccord avec la directive européenne. Le Medicine in the 21st Century, December 4–5, 1998, 2nd
nomic environment that includes various Monde 15 June (2000). edn 47–53 (AACC, Washington DC, 1998).
social values, research practices and business 7. Kolata, G. Special Report: Who owns your genes? New 26. Caulfield, T. & Gold, E. R. Genetic testing, ethical
York Times 15 May (2000). concerns, and the role of patent law. Clin. Genet. 57,
pressures. We are mindful that, in some situa- 8. Ramirez, A. School given patent to clone humans. 370–375 (2000).
tions, modifying patent law may reduce one National Post 16 May (2000). 27. Bruzzone, L. The research exemption: a proposal. Am.
9. Sagar, A., Daemmrich, A. & Ashiya, M. The tragedy of Intell. Prop. Law Assoc. QL 21, 52 (1993).
problem (such as permitting more competi- commoners: biotechnology and its publics. Nature 28. Parker, D. Patent infringement exemptions for life science
tion), while magnifying others (such as Biotechnol. 18, 2–4 (2000). research. Houston J. Intl Law 16, 615 (1994).
10. Angell, M. Is academic medicine for sale? N. Engl. J. 29. Gold, E. R. in Commercialization of Genetic Research:
reducing incentives to conduct research and Med. 20, 1516–1518 (2000). Ethical, Legal and Policy Issues (eds Caulfield, T. &
development). Nevertheless, although care 11. Pottagem, A. The inscription of life in law: gene, patents, Williams–Jones, B.) 63–78 (Plenum, New York, 1999).
and bio-politics. The Modern Law Review 61, 740–765 30. Schissel, A., Merz, J. F. & Cho, M. K. Survey confirms
must be taken, this debate needs to progress (1998). fear about licensing of genetic tests. Nature 402, 118
to ensure that patenting practices, as applied 12. Gold, E. R. Body Parts: Property Rights and the (1999).
Ownership of Human Biological Materials (Georgetown 31. Blumenthal, D. et al. Withholding Research Results in
to genetic material, fulfil the ultimate objec- Univ. Press, Washington DC, 1996). Academic Life Science: Evidence From a National Survey
tive of encouraging the development of 13. Caulfield, T. & Gold, E. R. Whistling in the wind: reframing of Faculty J. Am. Med. Assoc. 277, 1224 (1997).
the genetic patent debate. Forum for Applied Research 32. Caulfield, T. The commercialization of human genetics: a
genetic technologies into products for the and Public Policy 15, 75–79 (2000). discussion of issues relevant to Canadian consumers. J.
public’s good. 14. Ernst and Young’s Fourth Report on the Canadian Consumer Policy 21, 483–526 (1998).
Biotechnology Industry. Can. Biotechol. ‘97: Coming of 33. Packer, K. & Webster, A. Patenting culture in science:
Age (Ernst and Young, 1997). reinventing the scientific wheel of credibility. Science,
Update – note added in proof 15. President and Fellows of Harvard v. Commissioner of Technology and Human Values 21, 425–445
Patents (August 3, 2000) No. A-334–398 (Fed. Crt of (1996).
The recent announcement that scientists Appeals). 34. Blumenthal, D. Academic–industry relationships in the life
will share a patent over a disease-related 16. Nottingham, S. Eat Your Genes (St. Martin’s, New York, sciences. J. Am. Med. Assoc. 268, 3344 (1992).
1999). 35. Straus, J. Intellectual property issues in genome
gene43 with a patient advocacy group, who 17. Roberts, T. Why not patent plants? Patent World 113, research. Genome Digest 3, 1–2 (1996).
provided the researchers with blood and 14–16 (1999). 36. Barton, J. Reforming the patent system. Science 287,
18. Schehr, R. & Fox, J. Human genome bombshell. Nature 1933–1934 (2000).
tissue samples 44, is a positive sign that Biotechnol. 18, 365 (2000). 37. United States Patent and Trade Mark Office. Interim Utility
researchers take seriously their moral 19. Marcus, A. Owning a gene: patent pending. Nature Med. Guidelines (1999).
2, 728–729 (1996). 38. Holtzman, N. Are genetic tests adequately regulated?
responsibility to donors. Such steps are in 20. Nelkin, D. & Andrews, L. Homo economicus: Science 286, 409 (1999).
agreement with recent policy statements Commercialization of body tissue in the age of 39. Kodish, E. Commentary: Risks and benefits, testing and
biotechnology. Hastings Center Report 28, 30–39 (1998). screening, cancer, genes and dollars. J. Law Med. Ethics
issued by HUGO45. Binding legal measures 21. Heller, M. & Eisenberg, R. Can patents deter innovation? 25, 252–255 (1997).
would help to ensure that researchers and The anticommons in biomedical research. Science 280, 40. Brower, V. News: Testing, testing, testing? Nature Med.
698–701 (1998). 3, 131–132 (1997).
companies who comply with this type of 22. Knoppers, B. M. Status, sale and patenting of human 41. Weiss, R. Genetic testing’s human toll. Washington Post
ethical norm do not face unfair competi- genetic material: an international survey. Nature Genet. 21 July (1999).
22, 23–26 (1999). 42. Cowan, D. Tort liability of patentee licensors. J. Patent
tion from those who do not. 23. Bunk, S. Researchers feel threatened by disease gene Office Soc. 64, 87–104 (1982).
patents. The Scientist 13, 7 (1999) 43. Le Saux, O. et al. Mutations in a gene encoding an ABC
Timothy Caulfield is at the Health Law Institute, 24. Academy of Clinical Laboratory Physicians and transporter cause pseudoxanthoma elasticum. Nature
University of Alberta, Edmonton, Alberta, T6G Scientists. ACLPS Resolution: Exclusive Licenses for Genet. 25, 223–227 (2000).
2H5, Canada. E. Richard Gold is at the Faculty of Diagnostic Tests Approved by the ACLPS Executive 44. Smaglik, P. Tissue donors use their influence in deal over
Council 06/03/99 (1999). gene patent terms. Nature 407, 821 (2000).
Law, University of Western Ontario, London http://depts.washington.edu/labweb.aclps/license/htm 45. Human Genome Organization Ethics Committee. Genetic
Ontario, N6A 3K7 , Canada. Mildred K. Cho is at 25. Cho, M. K. in Preparing for the Millennium: Laboratory benefit sharing. Science 290, 49 (2000).
the Center for Biomedical Ethics, Stanford
University, Stanford, California 94304 , USA.
Correspondence to : tcaulfld@law.ualberta.ca
Links
TIMELINE
DATABASE LINKS BRCA1 | APOE
FURTHER INFORMATION American College of
Medical Genetics | Unesco’s 1997 Universal
Declaration on the Human Genome and
The origins of bioinformatics
Human Rights | European Patent Office |
United States Patent Office | Canadian Patent Joel B. Hagen
Office | Japanese Patent Office | patent on the
‘onco-mouse’ | European Patent Convention | Bioinformatics is often described as being internet and supercomputers1–3. However,
Incyte Pharmaceuticals | United States in its infancy, but computers emerged as some scientists who claim that bioinformatics
Supreme court case of Diamond versus important tools in molecular biology during is in its infancy acknowledge that computers
Chakrabarty | United States Patent Office’s the early 1960s. A decade before DNA were important tools in molecular biology a
recent interim guidelines sequencing became feasible, decade before DNA sequencing became feasi-
1. Rifkin, J. The Biotech Century (Penguin Putnam, New computational biologists focused on the ble4. Although the pioneers of computational
York, 1998). rapidly accumulating data from protein biology did not use the term ‘bioinformatics’
2. American College of Medical Genetics, Position
Statement on Gene Patents and Accessibility of Gene biochemistry. Without the benefits of to describe their work, they had a clear vision
Testing (1999). www.faseb.org/genetics/acmg/pol- supercomputers or computer networks, of how computer technology, mathematics
34.htm
3. Sarma, L. Biopiracy: Twentieth century imperialism in the these scientists laid important conceptual and molecular biology could be fruitfully
form of international agreements. Temple International
and Comparative Law Journal 13, 107–136 (1999).
and technical foundations for combined to answer fundamental questions
4. Thomas, S. et al. Ownership of the human genome. bioinformatics today. in the life sciences.
Nature 380, 387–388 (1996).
5. Thomas, S. in The Commercialization of Genetic
Three important factors facilitated the
Research: Ethical, Legal and Policy Issues (eds Caulfield, It is tempting to trace the origins of bioinfor- emergence of computational biology during
T. & Williams-Jones, B.) 55–62 (Kluwer
Academic/Plenum Publishing, New York, 1999).
matics to the recent convergence of DNA the early 1960s. First, an expanding collection
6. Nau, J. Y. Brevetabilité des gènes humains: le comité sequencing, large-scale genome projects, the of amino-acid sequences provided both a
developed from weapons research pro- cerns were “blown away” by Sanger’s work,
grammes during the Second World War, which quickly dispelled any doubts that
finally became widely available to academic each protein was characterized by a unique
biologists. Not all biologists had — or wanted primary structure11.
to have — access to these machines but, by Sequencing insulin was a case of problem
1960, scarcity of computers was no longer a solving by a master chemist who used great
serious stumbling block for the development scientific skill in separating and identifying the
of computational biology. fragments of protein degradation12. At the
same time, however, other biochemists were
Sequencing proteins developing more refined methods that would
The idea that proteins carry information transform the laborious analytical process
encoded in linear sequences of amino acids is used by Sanger and his co-workers. The
commonplace today, but it has a relatively Edman degradation reaction, by which bio-
short history. This idea first emerged during chemists could sequentially remove and iden-
the decades following the Second World War, tify individual amino acids from the amino
a time that one main participant, Emil Smith, terminus of a short peptide, was a great
later described as a “heroic period” in protein improvement over the more tedious methods
biochemistry8. The watershed event of this used by Sanger8,9. The use of ion exchange
Figure 1 | Frederick Sanger at the Nobel prize period was the first successful sequencing of a columns and other innovations in CHROMATOG-
ceremony in 1980. complete protein, INSULIN, by Frederick Sanger RAPHY and electrophoresis also made sequenc-
(Photograph kindly provided by the MRC, Laboratory
of Molecular Biology, Cambridge, UK.) and his colleagues8–10 at Cambridge University ing more efficient. Just as significantly, the
during the decade 1945–1955 (FIG. 1). entire process of separating and identifying
Sanger’s achievement, for which he was amino acids was rapidly becoming automated.
source of data and a set of interesting prob- awarded the 1958 Nobel Prize in chemistry, Using semi-automated techniques, researchers
lems that were infeasible to solve without the firmly established the polypeptide theory of led by Stanford Moore and William Stein at
number-crunching power of computers. protein structure. First formulated in 1902, the Rockefeller Institute were able to sequence
Second, the idea that macromolecules carry this theory had faced considerable scepti- the 124 amino acids in RIBONUCLEASE in about
information became a central part of the con- cism and competition from alternative the- half the time that Sanger’s group had spent
ceptual framework of molecular biology. ories9 (FIG. 2). Analytical techniques in pro- deciphering the sequence of the 51 amino
Although some historians and philosophers tein biochemistry had improved greatly acids in insulin13,14. Automation sent a shock
have questioned the theoretical significance of during the 1930s and 1940s, but before wave through the biochemical community,
this idea for modern molecular biology5–7, it Sanger’s work, practically nothing was because it promised to transform sequencing
seems likely that thinking in terms of macro- known about the order of amino acids in into a routine procedure carried out, not by
molecular information provided an impor- any protein. One could, therefore, still cling master chemists, but by competent laboratory
tant conceptual link between molecular biol- to the belief that proteins were structurally technicians8. By the late 1960s, Pehr Edman
ogy and the computer science from which simple or even that they had no definite had designed the ‘sequenator’, a fully automat-
formal information theory had arisen. Third, structure at all. As the biochemist Paul ed sequencing machine that implemented his
high-speed digital computers, which had Zamecnik later recalled, these lingering con- already widely used degradation reaction15.
Immunoglobulin
Insulin (α-chain) Glucagon Cytochrome c Lysozyme Trypsinogen (γ-chain)
21 29 105 129 216 446
1951 1953 1957 1960 1961 1962 1963 1965 1966 1967 1969
*The complete primary structure of insulin, including the positions of the disulphide bonds, was published in 1955.
(Dates in parentheses are for revisions of the originally published sequences; numbers in bold are the numbers of amino acids.)
Source: L.R. Croft, Handbook of Protein Sequence Analysis: A Compilation of Amino Acid Sequences of Proteins with an Introduction to the Methodology (John Wiley, Chichester, 1980).
became more commonly referred to as mole- have emphasized the importance of instru- trated by the career of Margaret Oakley
cular evolutionists, had several approaches at mentation8,9,19 but, with the exception of John Dayhoff31,32. Trained in quantum chemistry
their disposal. Comparisons of similar pro- Kendrew’s use of computers for elucidating and mathematics, she became interested in
teins, such as myoglobin and haemoglobin, the three-dimensional structure of proteins and molecular evolution around
provided evidence for molecular evolution by myoglobin18,27, the historical role of digital 1960. As associate director of the newly estab-
gene duplication. Comparison of homolo- computers during the 1960s has been virtual- lished National Biomedical Research
gous proteins drawn from various species ly ignored. Even in the case of Kendrew, com- Foundation, an organization founded specifi-
could be used to trace phylogenetic relation- puters have not been viewed as contributing cally to encourage the development of com-
ships among both the proteins themselves decisively to the discovery process. puter applications, Dayhoff was well situated
and the species that carried them. In some Nonetheless, digital computers were well suit- to explore mathematical approaches for
cases, such comparisons could also be used to ed to deal with the types of numerical data analysing amino-acid sequence data (FIG. 4).
recreate the ancestral proteins from which that protein biochemists were generating in Continuously funded by grants from the
present-day molecules evolved. Assuming growing amounts. National Institutes of Health throughout the
that amino-acid substitution rates were rela- By the early 1960s, computers were becom- 1960s and with further support from the
tively constant within a given protein, paleo- ing widely available to academic researchers. National Science Foundation, the National
geneticists had a ‘MOLECULAR CLOCK’ by which According to surveys conducted at the begin- Aeronautics and Space Administration, and
evolutionary events might be reliably dated. ning of the decade, 15% of colleges and univer- the IBM corporation, Dayhoff moved on sev-
These claims, particularly the idea of a sities in the United States had at least one com- eral fronts. Her initial project was writing a
molecular clock, were enormously controver- puter on campus, and most principal research series of FORTRAN programs to determine
sial and provided a source of conflict between universities were purchasing so-called ‘second the amino-acid sequences of protein mole-
molecular evolutionists and traditional natu- generation’ computers, based on transistors, to cules33,34. Taking the overlapping peptide frag-
ralists22–24. Sequence analysis also had to com- replace the older vacuum-tube models28. The ments from the partial digestion of a protein,
pete with well-established molecular tech- first high-level programming language, FOR- the programs deduced all of the possible
niques, such as the immunological measures TRAN (formula translation), was introduced sequences that were consistent with the data.
used by Morris Goodman, Allan Wilson, by the International Business Machines (IBM) Conceptually similar to the puzzle-solving
Vincent Sarich and others to unravel phylo- corporation in 1957. It was particularly well approach that biochemists claimed to have
genetic relationships23. Encounters among suited to scientific applications, and compared used in the early sequencing investigations of
competing groups of biologists at profes- with the earlier machine languages, it was rela- insulin and ribonuclease10,13,14,35, Dayhoff ’s
sional meetings could be bruising, but these tively easy to learn. For the first time, detailed computer programs arrived at the correct
confrontations should not eclipse the knowledge of computer architecture was not sequence for a small protein (ribonuclease)
important synthesis of evolutionary biology, needed to write a computer program. This within a few minutes. The same feat had
protein biochemistry and computer science important innovation in computer software taken a team of humans many months to
that was beginning to emerge during the early encouraged the growth of computational biol- accomplish. Similar programs written by
1960s, which laid an evolutionary foundation ogy. At the same time, there was a concerted other computational biologists at about the
for the bioinformatics of today24–26. effort by governmental agencies and the com- same time claimed to successfully sequence
puter industry to foster the development of hypothetical proteins up to 750 amino acids
Emergence of computational biology academic computing in the life sciences29,30. in length36. Significantly, even during the early
Historical studies of protein biochemistry The attraction of computers is well illus- development of these programs, Dayhoff and
her contemporaries realized that the logic of
Glossary sequence analysers could also be directly
CHROMATOGRAPHY
applied to nucleic acids when gene sequences
insulin-dependent diabetes mellitus.
A chemical analysis technique that uses a process of finally became available.
separating gases, liquids or solids from mixtures or MOLECULAR CLOCK Computer programs for sequence analysis
solutions by selective adsorption. The hypothesis that, in any given gene or DNA followed the principles initiated by the auto-
sequence, mutations accumulate at an approximately matic amino-acid analyser used by Stein and
CYTOCHROMES constant rate in all evolutionary lineages as long as the
Proteins whose function is to carry electrons or protons gene or the DNA sequence retains its original function.
Moore37,38. In both cases, the objective was to
(hydrogen ions) by virtue of the reversible develop quickly a library of sequences that
charging/discharging of an iron atom or iron/sulphur MYOGLOBIN could be used for studies in comparative bio-
atoms in the centre of the protein. Cytochromes are An oxygen-carrying muscle protein that makes oxygen chemistry and molecular evolution. To pro-
central molecules of electron transport in the process available to the muscles for contraction.
known as oxidative phosphorylation. Cytochromes are
mote this end, Dayhoff established the Atlas of
divided into four groups (a, b, c, d) according to their RIBONUCLEASE Protein Sequence and Structure, an annual
ability to absorb or transmit certain colours of light. A enzyme that hydrolyses RNA. publication that attempted to catalogue all
known amino-acid sequences. Although
HAEMOGLOBIN X-RAY CRYSTALLOGRAPHY
rudimentary by today’s standards, the Atlas
Protein present in red blood cells that reversibly binds Study of the molecular structure of crystalline
oxygen for transport to tissues. compounds through X-ray diffraction techniques.
served as the first database for molecular biol-
When an X-ray beam bombards a crystal, the atomic ogy, and it became an indispensable resource
INSULIN structure of the crystal causes the beam to scatter for early computational research25,31,32,39. It
A protein hormone secreted by β cells of the pancreas. (diffract) in a specific pattern. X-ray crystallography eventually evolved into a major online data-
Insulin is important in the regulation of glucose provides information on the positions of individual
metabolism, generally promoting the cellular use of
base, the Protein Information Resource (PIR),
atoms in the crystal, the distances between atoms, the
glucose. It is also an important regulator of protein and angles of the atomic bonds and other features of established in 1983, and it provided an
lipid metabolism. Insulin is used as a drug to control molecular geometry. important point of departure for other com-
Conclusions 13. Stein, W. H. & Moore, S. The chemical structure of 87–98 (1983).
proteins. Sci. Am. 204, 81–92 (1961). 32. Hunt, L. T. Margaret Oakley Dayhoff, 1925–1983. Bull.
By 1970, computational biologists had devel- 14. Moore, S. & Stein, W. H. Chemical structures of Math. Biol. 46, 467–472 (1984).
oped a diverse set of techniques for analysing pancreatic ribonuclease and deoxyribonuclease. Science 33. Dayhoff, M. O. & Ledley, R. S. Comprotein: A computer
180, 458–464 (1973). program to aid primary protein structure determination.
molecular structure, function and evolution. 15. Edman, P. & Begg, G. A protein sequenator. Eur. J. Proc. Fall Joint Comp. Conf. 22, 262–274 (1962).
Although originally designed for studying Biochem. 1, 80–91 (1967). 34. Dayhoff, M. O. Computer aids to protein sequence
16. Sanger, F. Sequences, sequences, and sequences. determination. J. Theor. Biol. 8, 97–112 (1965).
proteins, many of these computing tech- Annu. Rev. Biochem. 57, 1–28 (1988). 35. Thompson, E. O. The insulin molecule. Sci. Am. 192,
niques could be adapted for studying nucleic 17. Anfinsen, C. B. Principles that govern the folding of 36–41 (1955).
protein chains. Science 161, 223–230 (1973). 36. Bernhard, S. A., Bradley, D. F. & Duda, W. L. Automatic
acids. Some of these techniques survive today 18. Olby, R. C. The ‘Mad Pursuit’: X-Ray crystallographers’ determination of amino acid sequences. IBM J. Res. Dev.
or have lineal descendants that are used in search for the structure of hemoglobin. Hist. Phil. Life Sci. 7, 246–251 (1963).
7, 171–193 (1985). 37. Spackman, D. D., Stein, W. H. & Moore, S. Automatic
bioinformatics. In other cases, they stimulat- 19. Kay, L. The Molecular Vision of Life (Oxford Univ. Press, recording apparatus for use in the chromatography of
ed the development of more refined tech- New York, 1993). amino acids. Anal. Chem. 30, 1190–1206 (1958).
20. Srinivasan, P. R., Fruton, J. S. & Edsall, J. T. (eds) The 38. Mason. E. E. & Bulgren, W. G. Computer Applications in
niques to correct deficiencies in the original Origins of Modern Biochemistry: A Retrospective on Medicine (Charles C. Thomas, Springfield, Illinois, 1964).
methods. Although the nascent field was later Proteins (New York Academy of Sciences, New York, 39. Fitch, W. M. Book review of M. O. Dayhoff, Atlas of
1979). Protein Sequence and Structure. Syst. Zool. 22, 196
revolutionized by the advent of genome pro- 21. Zuckerkandl, E. & Pauling, L. Molecules as documents of (1972).
jects, large-scale computer networks, evolutionary history. J. Theor. Biol. 8, 357–366 (1965). 40. Doolittle, R. F. Some reflections on the early days of
22. Zuckerkandl, E. On the molecular evolutionary clock. J. sequence searching. J. Mol. Med. 75, 239–241 (1997).
immense databases, supercomputers and Mol. Evol. 26, 34–64 (1987). 41. Doolittle, R. F. & Blombäck, B. Amino-acid sequence
powerful desktop computers, today’s bioin- 23. Dietrich, M. Paradox and persuasion. Negotiating the investigations of fibrinopeptides from various mammals:
place of molecular evolution within evolutionary biology. Evolutionary implications. Nature 202,147–152 (1964).
formatics also rests on the important intellec- J. Hist. Biol. 31, 85–111 (1998). 42. Fitch, W. M. & Margoliash, E. Construction of
tual and technical foundations laid by scien- 24. Hagen, J. B. Naturalists, molecular biologists, and the phylogenetic trees. Science 155, 279–284 (1967).
challenges of molecular evolution. J. Hist. Biol. 32, 43. Eck, R. V. & Dayhoff, M. O. Atlas of Protein Sequence
tists at an earlier period in the computer era. 321–341 (1999). and Structure (National Biomedical Research Foundation,
25. Jungck, J. R. & Friedman, R. M. Mathematical tools for Silver Spring, Maryland, 1966).
Joel B. Hagen is at the Department of Biology,
molecular genetics data: An annotated bibliography. Bull. 44. Dayhoff, M. O. Computer analysis of protein evolution.
Radford University, Radford, Virginia 24142, Math. Biol. 46, 699–744 (1984). Sci. Am. 221, 87–95 (1969).
USA. e-mail: jhagen@radford.edu 26. Hagen, J. B. The introduction of computers into 45. Fitch, W. M. An improved method of testing for
systematic research in the United States during the evolutionary homology. J. Mol. Biol. 16, 9–16 (1966).
1960s. Studies Hist. Phil. Biol. Biomed. Sci. (in the press). 46. Dayhoff, M. O. & Eck, R. Atlas of Protein Sequence and
Links 27. Perutz, M. Early days of protein crystallography. Meth. Structure 1967–1968 (National Biomedical Research
Enzymol. 114, 3–18 (1985). Foundation, Silver Spring, Maryland, 1968).
DATABASE LINKS insulin | ribonuclease | 28. Anonymous. Computing in the university. Datamation 8, 47. Needleman, S. B. & Wunsch, C. D. A general method
27–30 (1962). applicable to the search for similarities in the amino acid
myoglobin | haemoglobin | Protein 29. Ledley, R. S. Digital electronic computers in biomedical sequence of two proteins. J. Mol. Biol. 48, 443–453
Information Resource | cytochrome c sciences. Science 130, 1225–1234 (1959). (1970).
30. Ledley, R. S. Use of Computers in Biology and Medicine 48. Levinthal, C. Molecular model-building by computer. Sci.
FURTHER INFORMATION IBM history |
(McGraw–Hill, New York, 1965). Am. 214, 42–52 (1966).
National Biomedical Research Foundation | 31. Hunt, L. T. Margaret O. Dayhoff, 1925–1983. DNA 2,
History of visualization of biological
macromolecules
ENCYCLOPEDIA OF LIFE SCIENCES DNA
sequencing | Sanger, Frederick | Protein
secondary structures: predictions | Molecular TIMELINE
clocks | Linus Carl Pauling