How much can biochemistry change in half a century?
While browsing older scientific books at the Toyonaka Campus library of Osaka University, I came across Seikagaku Nyumon [Introduction to Biochemistry] by Yo Imai, published by Asakura Shoten. Its first edition was published in 1974, and the copy examined here is a 1977 reprint.
More than 50 years have passed since the book first appeared. One might expect a biochemistry textbook from that era to be filled with obsolete pathways and discarded concepts.
Reading its chapter on carbohydrate metabolism, however, gives a very different impression.
The glycolytic pathway itself looks remarkably familiar.
At the same time, some statements clearly reflect an earlier stage of biochemical knowledge. Complete glucose oxidation is described as yielding 38 ATP. Growth hormone appears in a description of blood glucose regulation that differs from the way its metabolic effects are usually presented today. Cancer cells already appear in the discussion of glycolysis, but modern cancer metabolism gives that observation a much deeper meaning.
Using this 1974 textbook as a window into the past, let us ask a simple question: what has changed in carbohydrate metabolism over the past 50 years, and what has surprisingly stayed the same?
1. Carbohydrate Metabolism in 1974
Chapter 7 of the textbook is devoted to carbohydrate metabolism.
It begins with a story that remains familiar today. Dietary carbohydrates are digested into smaller sugars such as glucose. Absorbed glucose reaches the liver through the portal circulation, where it can be stored as glycogen or released into the circulation. When energy is required, carbohydrate is oxidized and ATP is produced.
The broad outline has aged remarkably well.
The differences become more interesting when we examine the details.
2. Intestinal Glucose Absorption: The Principle Was Already There
The textbook explains that intestinal sugar absorption cannot be understood by simple diffusion alone. It describes the importance of Na+ for active sugar uptake and an ATP-dependent Na+ pump that maintains the required ion gradient.
This description is more than 50 years old, yet the underlying principle remains recognizable.
Today, we can assign specific molecular components to this process. In the small intestine, SGLT1 transports glucose together with Na+ across the apical membrane of enterocytes. The driving Na+ gradient is maintained by the basolateral Na+/K+-ATPase, while glucose exits toward the bloodstream mainly through GLUT2.
In this case, half a century of research did not overturn the basic mechanism.
Instead, the molecular machinery behind the mechanism became much more clearly defined.
3. An Unexpected Statement About Growth Hormone
The textbook's discussion of blood glucose regulation is also largely recognizable. Glycogen breakdown and glucose production contribute to increasing blood glucose, while glucose utilization contributes to lowering it. Insulin, glucagon, epinephrine, and adrenal hormones all appear in the discussion.
Then comes a statement that looks unusual from a modern perspective.
The 1974 textbook groups growth hormone together with insulin as acting in the direction of lowering blood glucose.
Modern physiology presents a more complicated picture. Growth hormone can directly antagonize insulin action and promote insulin resistance, particularly during sustained GH exposure. In contrast, IGF-I, whose production is stimulated by GH, can exert insulin-like metabolic effects.
The metabolic effects of the GH–IGF axis therefore cannot be summarized simply as a single glucose-lowering action.
This is a good example of why reading an old textbook is scientifically interesting. The goal is not simply to find an old statement and label it as wrong. Instead, the comparison shows how physiological interpretation changes as mechanisms become better understood.
4. Opening the Glycolysis Pathway
The most striking comparison begins when the textbook reaches glycolysis.
The pathway is introduced as the Embden–Meyerhof pathway and follows the familiar sequence from glucose to pyruvate:
Glucose → glucose-6-phosphate → fructose-6-phosphate → fructose-1,6-bisphosphate → triose phosphates → 1,3-bisphosphoglycerate → 3-phosphoglycerate → 2-phosphoglycerate → phosphoenolpyruvate → pyruvate.
The major enzymes are equally recognizable: hexokinase, phosphofructokinase, aldolase, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase, enolase, and pyruvate kinase.
Some terminology and notation differ from modern conventions, but the biochemical sequence itself is immediately recognizable.
The central map of glycolysis has barely changed.
This is perhaps the most surprising lesson from opening a textbook published more than half a century ago. The old pathway does not look like an abandoned version of glycolysis. It looks very much like glycolysis as students still learn it today.
5. The Net ATP Yield Is Still Two
The ATP accounting is equally familiar.
The textbook describes ATP consumption in the early reactions of glycolysis and ATP production later in the pathway. Because two ATP molecules are consumed and four are subsequently produced per glucose, the final result is a net gain of two ATP molecules.
This has not changed.
A student studying glycolysis in 1974 and a student studying it in 2026 therefore arrive at the same fundamental result:
Glycolysis produces a net 2 ATP per glucose.
Considering how much molecular biology and biochemistry have advanced since the 1970s, the stability of this basic pathway and its energy accounting is striking.
6. But on the Same Page: 38 ATP
Then the textbook suddenly reminds us that it was written in 1974.
When comparing glycolysis with complete oxidation of glucose, the book gives a total yield of 38 ATP per glucose.
This number will look familiar to anyone who learned biochemistry from older textbooks. Modern treatments, however, generally estimate approximately 30–32 ATP from complete aerobic oxidation of one glucose molecule in a eukaryotic cell.
Where did the missing ATP go?
The answer is not that scientists discovered a completely different glycolytic pathway. Instead, the quantitative understanding of oxidative phosphorylation changed.
Older textbook calculations commonly assigned approximately 3 ATP to each NADH and 2 ATP to each FADH2. Modern estimates are closer to approximately 2.5 ATP per NADH and 1.5 ATP per FADH2.
The total ATP yield can also vary depending on how reducing equivalents from cytosolic NADH generated during glycolysis are transferred into mitochondria. Different shuttle systems therefore contribute to the familiar range rather than a single universal integer.
The interesting point is that the glycolytic pathway itself did not need to be redrawn.
What changed was our quantitative understanding of how reducing power is converted into ATP.
7. Cancer Cells Were Already in the Glycolysis Chapter
Another fascinating passage appears in the textbook's discussion of glycolysis and energy production.
Glycolysis is described as a way to produce ATP rapidly under anaerobic conditions, and the discussion mentions vigorously contracting muscle, microorganisms living under anaerobic conditions, and cancer cells.
The association between cancer and glycolysis is therefore far from a recent idea.
Modern cancer metabolism, however, frames the phenomenon more precisely. The Warburg effect refers to the tendency of many cancer cells to consume large amounts of glucose and convert much of it to lactate even when oxygen is available. For this reason, the phenomenon is known as aerobic glycolysis.
Modern research has also moved beyond the simple question of ATP efficiency. Investigators now examine how aerobic glycolysis relates to NAD+ regeneration, redox balance, biosynthetic requirements, carbon allocation, signaling, and cell proliferation.
Importantly, cancer cells are not simply cells that have abandoned mitochondria. Mitochondrial metabolism remains important in many cancers.
The question has therefore evolved from:
“Cancer cells use glycolysis.”
to a much deeper question:
“Why do many proliferating cancer cells favor aerobic glycolysis even when oxygen is available?”
8. The Pyruvate Dehydrogenase Complex Was Already Remarkably Detailed
The next step in glucose oxidation is equally impressive.
The 1974 textbook illustrates the conversion of pyruvate to acetyl-CoA through the pyruvate dehydrogenase complex.
The diagram already contains the three major catalytic components of the complex together with familiar cofactors including TPP, lipoic acid, CoA, FAD, and NAD+.
These remain fundamental components of the modern biochemical description of the pyruvate dehydrogenase complex.
Today, structural biology can examine the organization, dynamics, substrate transfer, phosphorylation-dependent regulation, and molecular architecture of this enormous complex in far greater detail.
Yet its biochemical core was already present in a student textbook in 1974.
Again, the major change is not the fundamental reaction.
It is the resolution at which we can understand it.
9. Gluconeogenesis Was Not Simply Glycolysis in Reverse
The textbook also emphasizes another concept that remains central to modern biochemistry: glucose synthesis cannot be achieved simply by running every glycolytic reaction backward.
Some glycolytic reactions are strongly favorable in the forward direction and must be bypassed during gluconeogenesis.
Modern descriptions identify pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase, and glucose-6-phosphatase as the enzymes responsible for bypassing the three major irreversible steps of glycolysis.
Once again, the fundamental concept has survived the intervening half-century.
10. What Actually Changed in 50 Years?
Reading a 1974 biochemistry textbook produces an unexpected conclusion.
The most striking feature is not how primitive its metabolic pathways look.
It is how familiar they look.
| 1974 textbook | Modern biochemistry |
|---|---|
| Na+ is involved in intestinal glucose uptake | SGLT1, GLUT2, and Na+/K+-ATPase define the molecular mechanism |
| Blood glucose is tightly regulated | The same fundamental principle remains |
| Growth hormone is described as acting in the direction of lowering blood glucose | Direct GH effects and IGF-I effects are distinguished; sustained GH exposure can promote insulin resistance |
| Glycolytic pathway | The central pathway is essentially unchanged |
| Net glycolytic yield = 2 ATP | Still 2 ATP |
| Complete glucose oxidation = 38 ATP | Common modern estimates are approximately 30–32 ATP |
| Cancer cells associated with glycolysis | Aerobic glycolysis, the Warburg effect, and metabolic reprogramming are studied mechanistically |
| PDH complex and its major cofactors | Same biochemical core with much deeper structural and regulatory understanding |
| Gluconeogenesis is not simply reverse glycolysis | The same fundamental principle remains |
Biochemistry has changed enormously since 1974. But at least for central carbohydrate metabolism, the past half-century was not primarily a story of old pathway maps being discarded and replaced.
Many of the arrows were already there.
What changed dramatically was what we learned around those arrows: the molecular identity of transporters and regulators, the quantitative energetics of mitochondria, the structural organization of enzyme complexes, tissue-specific regulation, and the role of metabolism in diseases such as cancer.
Reading an old textbook is therefore not simply an exercise in finding outdated science.
It reveals something more interesting:
Which parts of the biochemistry we now take for granted have survived half a century—and which parts had to be rewritten?
That is the question we will continue to explore in Biochemistry Then and Now.
References
1. Imai Y. Seikagaku Nyumon [Introduction to Biochemistry]. Tokyo: Asakura Shoten; 1974.
2. Koepsell H. Glucose transporters in the small intestine in health and disease. Pflügers Archiv - European Journal of Physiology. 2020;472:1207–1248. doi:10.1007/s00424-020-02439-5.
3. Møller N, Jørgensen JOL. Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocrine Reviews. 2009;30(2):152–177. doi:10.1210/er.2008-0027.
4. Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th ed. New York: Garland Science; 2002. Chapter 14: The Mitochondrion.
5. Luengo A, Li Z, Vander Heiden MG. New Clarity on the Warburg Effect. National Cancer Institute; 2021.
6. Patel MS, Nemeria NS, Furey W, Jordan F. The pyruvate dehydrogenase complexes: structure-based function and regulation. Journal of Biological Chemistry. 2014;289(24):16615–16623. doi:10.1074/jbc.R114.563148.
7. Melkonian EA, Asuka E, Schury MP. Physiology, Gluconeogenesis. StatPearls. StatPearls Publishing.