Essay: The Relevance of Structural Molecular Biology to Medicine

The Relevance of Structural Molecular Biology to Medicine

A conceptual rendering of molecular medicine: a DNA double helix merges into a protein ribbon against an X-ray diffraction field, symbolising the continuum between structure and human health that defined early molecular biophysics at the University of Leeds (1992).

Author: Adisha Kariyawasam Molecular Biophysics, MScIT, PGCE (PCET), BCS

Originally written 15 November 1992, BSc (Hons) Molecular Biophysics, University of Leeds
Republished and expanded, 2025

Preface (2025 Edition)

This essay was originally written in November 1992 during my second year as an undergraduate in Molecular Biophysics at the University of Leeds. It reflects a formative period of my understanding of  structural biology, when the relationships between molecular structure and disease were first becoming clear through advances in X-ray crystallography, molecular genetics, and the emerging field of protein engineering.

At that time, the question “What is the relevance of structural molecular biology to medicine?” stood at the frontier of interdisciplinary science. The essay focuses on one particular area - oncology - as a way of exploring how the study of molecular architecture could illuminate the understanding and treatment of disease.

The Relevance of Structural Molecular Biology to Medicine

Introduction

Over the past decades, remarkable progress has been made in understanding the molecular structure of life. But what relevance does this have to medicine? It would be impossible to survey all aspects of molecular biology relevant to medical science; however, one field - oncology, the study of cancer - provides a compelling focus through which to examine the link between molecular structure and disease.

In the early days of structural biology, the physiologist Archibald Vivian Hill - Nobel laureate for his pioneering studies of muscle physiology - famously dismissed crystallography’s biological value with the remark:

“That’s no good - crystals don’t wriggle, and if they don’t wriggle, it’s not biology.”
(Hill, quoted in Perutz, 1987, p. 56)

Hill’s scepticism captured a prevailing sentiment: that static crystal structures could never explain the dynamic nature of living systems. Yet it was precisely through these “non-wriggling crystals” that the foundations of molecular medicine were laid, transforming the diagnosis and treatment of disease.

Molecular Biology and the Architecture of Life

Structural molecular biology seeks to unravel the atomic frameworks underpinning biological processes, linking the physical and chemical properties of macromolecules to their physiological roles. Within living cells, macromolecules - proteins, nucleic acids, carbohydrates, and lipids—interact to sustain life. These interactions determine how energy is transferred, how cells communicate, and how genetic information is expressed and regulated.

By elucidating molecular structure, scientists have uncovered the intimate relationship between form and function - a relationship that lies at the heart of all biological activity.

Molecular Recognition

The study of molecular recognition - how biological molecules identify and bind to specific partners - has revealed the intricate logic of life at the atomic scale. Enzyme catalysis, antigen–antibody specificity, and receptor–ligand interactions all depend on the precise folding of protein macromolecules.

For instance, the serine protease family (trypsin, chymotrypsin, and elastase) exhibits near-identical three-dimensional structures across widely differing organisms, despite variations in sequence. This conservation shows that evolution has optimised structural motifs for efficiency and resilience.

Biological systems therefore exhibit spatial and temporal molecular patterns: three-dimensional arrangements that define how and when biochemical events occur.

Macromolecules in Advanced Systems

Even the simplest living systems are molecularly complex. The nucleoprotein virus, for example, contains all the information necessary for self-replication - but only within a suitable cellular environment. Such simplicity belies extraordinary sophistication at the molecular level.

As evolution progressed, increased molecular complexity led to specialised structures, elaborate metabolic pathways, and finely tuned control systems. Medicine, by contrast, concerns itself with understanding and repairing these systems when they fail.

Molecular Function and Genetic Control

Our understanding of how complex macromolecules arise from simple precursors continues to grow. Nucleic acids store genetic information, while proteins act as catalysts, regulators, and structural elements. Together, they embody the central dogma of molecular biology—DNA makes RNA makes protein.

Environmental conditions can influence gene expression, as shown in tissue culture and embryonic transplantation experiments (Engström and Finean, 1969). Yet, despite these influences, the organism’s genetic material sets the boundaries for development and differentiation.

In this sense, medicine and molecular biology converge: both seek to understand how the expression of genetic information shapes health and disease.

Genetics and Disease

Molecular genetics has provided powerful techniques for studying human disease. The use of DNA probes, restriction enzyme mapping, and blotting techniques has made it possible to detect specific mutations responsible for inherited disorders. For example, changes in DNA restriction patterns can indicate chromosomal abnormalities or deletions.

Although these early methods were limited to detecting large alterations, they laid the groundwork for today’s genomic medicine. Questions about the role of non-coding DNA - the so-called C-value paradox - continue to inspire new discoveries, particularly in the regulation of gene expression.

Molecular Defects and Pathology

Pathological conditions often stem from molecular defects. In sickle-cell anaemia, a single amino-acid substitution (glutamic acid to valine at position six) in the β-chain of haemoglobin alters its structure, leading to polymerisation and reduced oxygen-binding capacity.

Analogously, a similar substitution (Glu¹²→Val) has been observed in the p21 protein isolated from bladder carcinoma cells (McKenna, 1983). In such cases, small molecular defects can have profound physiological consequences.

Moreover, some molecular defects render cells more sensitive to environmental factors, such as air pollutants or carcinogens, which may in turn trigger the onset of cancer.

Oncogenes and Oncoproteins

The discovery of oncogenes - mutated or overactive versions of normal cellular genes known as proto-oncogenes - has been one of the defining achievements of molecular medicine. Proto-oncogenes normally regulate cell growth and differentiation, but when activated through mutation, amplification, or chromosomal translocation, they can drive malignancy (Ellis and Sikora, 1987).

Their protein products, oncoproteins, act as molecular switches within complex signalling cascades. Through advances in oligopeptide immunisation and gene-shuffling, researchers have developed monoclonal antibodies (MCAs) that specifically target these oncoproteins (Evan, 1985; Roberts et al., 1987).

Recent innovations have gone further: immunotoxins, or “magic bullets,” combine monoclonal antibodies with toxins such as saporin, selectively recognising and destroying tumour cells expressing heat shock proteins (Poccia et al., 1992).

Such work exemplifies how structural molecular biology provides not only understanding but also intervention.

From Structure to Therapy

The union of structural insight and computational modelling has revolutionised therapeutic design. High-resolution crystallography, nuclear magnetic resonance (NMR) spectroscopy, and molecular dynamics simulations enable scientists to visualise the very interactions that determine drug efficacy and side effects.

These approaches have given rise to targeted therapies - small-molecule inhibitors, monoclonal antibodies, and engineered peptides - that treat disease with unprecedented precision. The concept that “structure determines function” is now the foundation of precision medicine.

Conclusion

Diseases often result from breakdowns in molecular coordination - defects in enzymatic control, signal transduction, or gene regulation. Structural molecular biology provides the means to identify, understand, and rectify these defects.

As Max Perutz (1989) observed, “protein structure holds the key to understanding disease.” The insights drawn from static crystal structures have revealed the underlying motions of life itself, proving A.V. Hill’s famous quip profoundly ironic. Crystals do “wriggle” - at least in the imagination of structural biologists - and through them, medicine has learned to see life at atomic resolution.

Afterword (2025 Reflection)

More than thirty years later, the themes explored in this essay have matured into the foundations of modern biomedicine. Structural molecular biology now extends far beyond the X-ray crystallography of the early 1990s. Techniques such as cryo-electron microscopy, single-molecule spectroscopy, and artificial intelligence–based protein folding have revealed biological detail once thought impossible.

Therapeutics based on monoclonal antibodies, protein engineering, and gene editing now routinely save lives. The “molecular keyboard” of oncogenes, once a research metaphor, has become a clinical reality through molecular diagnostics and personalised treatment.

What began as the study of static crystals has evolved into a science of living structure - a testament to the truth that, in biology, everything wriggles.

References (Harvard Format)

• Ellis, M. and Sikora, K. (1987) ‘Oncogenes and cancer: clinical implications’, Journal of the Royal College of Physicians of London, 21(2), pp. 122–127.

• Engström, L. and Finean, J.B. (1969) Biological Ultrastructure. London: Academic Press.

• Evan, G. (1985) ‘Molecular approaches to oncoprotein immunisation’, Molecular and Cellular Biology, 5, p. 3610.

• Hill, A.V. (quoted in Perutz, M.F. 1987) Is Science Necessary? Essays on Science and Scientists. Oxford: Oxford University Press, p. 56.

• Lasserre, C. et al. (1992) ‘Activation of the HIP gene in human primary liver cancer’, Cancer Research, 52(18), pp. 5089–5095.

• McKenna, P.G. (1983) ‘Molecular defects in bladder carcinoma’, Irish Medical Journal, 76(8), pp. 237–240.

• Perutz, M.F. (1989) Protein Structure: New Approaches to Disease and Therapy. Oxford: Oxford University Press.

• Poccia, F. et al. (1992) ‘Use of immunotoxins in targeting heat shock proteins in tumour cells’, British Journal of Cancer, 66(3), pp. 427–432.

• Roberts, S. et al. (1987) ‘Monoclonal antibody design using gene-shuffling techniques’, Nature, 328, pp. 731–733.

Appendix 1: Glossary of Key Terms

Term	Definition
Amino acid	The basic building block of proteins, consisting of an amino group, a carboxyl group, and a side chain (R group) that determines its chemical properties.
Antibody	A protein produced by the immune system that specifically recognises and binds to foreign antigens.
Central dogma	The fundamental principle of molecular biology: DNA → RNA → Protein.
Cryo-electron microscopy (cryo-EM)	A modern imaging technique that allows biological molecules to be visualised at near-atomic resolution without crystallisation.
DNA probe	A short, labelled DNA fragment used to detect complementary sequences in genetic analysis.
Gene expression	The process by which genetic information is transcribed and translated into proteins.
Macromolecule	A large molecule such as a protein, nucleic acid, or polysaccharide essential for life’s processes.
Monoclonal antibody (MCA)	An antibody produced by a single clone of cells, identical in structure and specificity, used in diagnostics and therapy.
Oncogene	A gene that has the potential to cause cancer when mutated or abnormally expressed.
Oncoprotein	The protein product of an oncogene, often involved in the regulation of cell growth and division.
Protein folding	The process by which a protein assumes its functional three-dimensional structure.
Proto-oncogene	A normal gene that can become an oncogene due to mutation or increased expression.
Restriction enzyme	A bacterial enzyme that cuts DNA at specific sequences, used in genetic mapping and molecular cloning.
Saporin	A ribosome-inactivating protein used in immunotoxins to destroy targeted cells.
Serine protease	A family of enzymes that use a serine residue in their active site to catalyse the cleavage of peptide bonds.
Structural molecular biology	The study of the molecular structure and physical properties of biological macromolecules.

Appendix 2: Short Biographies of Scientists Mentioned

Ellis, Michael (dates not publicly recorded)
Professor Michael Ellis is a British oncologist whose collaborative work with Karol Sikora in the 1980s helped bridge molecular biology and clinical cancer research. Their studies clarified the role of oncogenes in tumour formation and progression, contributing to early frameworks for precision medicine. Ellis co-authored the 1987 Journal of the Royal College of Physicians of London paper that emphasised the clinical potential of molecular insights into cancer.

Elion, Gertrude Belle (1918–1999)
Gertrude Elion was an American biochemist and pharmacologist whose pioneering use of rational drug design transformed modern therapeutics. Awarded the 1988 Nobel Prize in Physiology or Medicine, she developed life-saving drugs for leukaemia, herpes, and AIDS. Her emphasis on molecular mechanism and enzyme targeting anticipated the structure-based drug discovery approaches that underpin much of today’s biomedical research.

Engström, Lars (dates not publicly recorded)
Lars Engström was a Swedish biochemist known for his collaborative work with James B. Finean on cellular ultrastructure. Their 1969 text Biological Ultrastructure provided one of the earliest comprehensive analyses of how macromolecular organisation influences cell function. Engström’s work helped establish the conceptual bridge between cell morphology and molecular biophysics.

Evan, Geoffrey M. (born 1952)
Commonly known as Gerard Evan, this British molecular biologist is recognised for his research on oncogene function and apoptosis. His early 1980s work on molecular immunisation and oncoprotein regulation connected structural understanding with cancer immunotherapy. His 1985 paper in Molecular and Cellular Biology exemplified the shift toward translational research that merged molecular structure with medical application.

Finean, James B. (1913–1987)
James B. Finean was a British biophysicist who collaborated with Lars Engström on the study of cellular and membrane ultrastructure. Their joint work clarified how lipid and protein components assemble to form biological membranes, reinforcing the idea that biological form and molecular organisation are inseparable. Finean’s research influenced later developments in structural biology and membrane biophysics.

Hill, Archibald Vivian (1886–1977)
A.V. Hill was a pioneering British physiologist and one of the founders of biophysics. He was awarded the 1922 Nobel Prize in Physiology or Medicine (shared with Otto Meyerhof) for his discoveries on the production of heat in muscle. Hill’s quip, “That’s no good — crystals don’t wriggle, and if they don’t wriggle, it’s not biology,” reflected his early scepticism toward crystallography. Ironically, his emphasis on quantitative methods and physical principles paved the way for modern molecular physiology.

Kendrew, John Cowdery (1917–1997)
John Kendrew was a British biochemist and structural biologist who, together with Max Perutz, shared the 1962 Nobel Prize in Chemistry for their elucidation of the structures of globular proteins via X-ray crystallography. His model of myoglobin was the first atomic-resolution protein structure ever determined. Kendrew’s achievements validated the power of crystallography to reveal biological function, contradicting Hill’s famous assertion.

Lasserre, Charles (dates not publicly recorded)
Dr Charles Lasserre was a French cancer researcher active during the late 1980s and early 1990s. His team’s work on the HIP gene in human liver cancer (published in Cancer Research, 1992) provided early molecular evidence of gene activation in oncogenesis. Lasserre’s studies contributed to the growing understanding of genetic regulation in tumour biology.

McKenna, Peter G. (dates not publicly recorded)
Dr Peter G. McKenna was an Irish clinician and molecular biologist whose research in the early 1980s explored molecular defects in human cancers. His 1983 Irish Medical Journal paper on bladder carcinoma demonstrated how specific amino acid substitutions in proteins could influence tumour development. McKenna’s work exemplified the clinical application of molecular genetics to pathology.

Perutz, Max Ferdinand (1914–2002)
Max Perutz was an Austrian-born British molecular biologist who pioneered the field of protein crystallography. He shared the 1962 Nobel Prize in Chemistry with John Kendrew for determining the structure of haemoglobin. Perutz’s later works, including Is Science Necessary? (1987) and Protein Structure: New Approaches to Disease and Therapy (1989), reflected deeply on the social and medical dimensions of molecular science. His research revealed how structural changes in proteins underpin both normal physiology and disease.

Poccia, Federico (1948–2004)
Federico Poccia was an Italian biochemist whose research advanced understanding of immunotoxins and immune cell development. His 1992 British Journal of Cancer paper explored the use of monoclonal antibodies conjugated with toxins to target tumour-specific heat shock proteins. Poccia’s work exemplified the move from molecular understanding to molecular therapeutics.

Roberts, Stephen (dates not publicly recorded)
Stephen Roberts is a molecular biologist best known for his late-1980s work on recombinant antibody design and gene-shuffling, published in Nature. His research contributed to the evolution of monoclonal antibody technology and the concept of engineered immunotherapy, bridging molecular structure and clinical application.

Sikora, Karol (born 1948)
Professor Karol Sikora is a British oncologist, medical educator, and cancer policy advocate. As co-author of early papers on oncogenes with Michael Ellis, Sikora was instrumental in linking molecular mechanisms with clinical oncology. He later served as Director of the WHO Cancer Programme. Sikora’s career exemplifies the translation of molecular biology into evidence-based cancer treatment.

Wrighton, Stephen A. (1951– )
While not a direct source in the essay, Stephen Wrighton’s contributions to molecular pharmacology during the late 1980s - particularly in cytochrome P450 enzyme characterisation - represent the broader scientific milieu of structural molecular medicine. His work exemplified the biochemical precision the essay advocates, where understanding enzyme structure informs pharmacological design.

Disclaimer

The views, interpretations, and reflections expressed in this essay are those of the author A. Kariyawasam and do not necessarily represent the positions or opinions of staff at the University of Leeds or any affiliated institution.