In the early $20^\text{th}$ century, biologists knew that traits were inherited, but they did not know which chemical molecule carried this genetic information. The candidates were proteins (complex and abundant) and deoxyribonucleic acid ($\text{DNA}$), which was considered too simple to encode heredity. The critical shift in understanding began with the work of Frederick Griffith and culminated in the definitive experiments of Oswald Avery, proving that DNA is the ultimate molecule of inheritance, a discovery that paved the way for Watson and Crick's structural model (Article 6).

The British bacteriologist Frederick Griffith conducted experiments using two strains of the bacterium Streptococcus pneumoniae (which causes pneumonia in mice):

• S (Smooth) Strain: Virulent (deadly), protected by a polysaccharide capsule.

• R (Rough) Strain: Non-virulent (harmless), lacks the capsule.

Griffith performed four key injections on mice:

1. Live R Strain: Mouse lives. (Harmless)

2. Live S Strain: Mouse dies. (Deadly)

3. Heat-Killed S Strain: Mouse lives. (Deadly substance is destroyed)

4. Heat-Killed S Strain + Live R Strain: Mouse dies.

• The Shocking Result: From the dead mouse in the fourth group, Griffith recovered live S-strain bacteria. Somehow, the harmless $\text{R}$ bacteria had acquired the genetic trait (the ability to produce a capsule) from the dead $\text{S}$ bacteria.

• The Conclusion: Griffith proposed that a substance, which he called the "transforming principle," was transferred from the dead virulent cells to the live non-virulent cells, genetically changing (transforming) them. The chemical nature of this principle remained unknown.

Fifteen years later, at the Rockefeller Institute, Oswald Avery, Colin MacLeod, and Maclyn McCarty undertook the complex task of identifying Griffith's transforming principle.

• The Method: They took the heat-killed $\text{S}$ cells and used enzymes to systematically destroy one class of biomolecule at a time (proteins, $\text{RNA}$, $\text{DNA}$, lipids) before mixing the remnants with the live $\text{R}$ cells.

• The Critical Test: They used the enzyme DNase to destroy the $\text{DNA}$ in the $\text{S}$ cell extract. When the $\text{DNA}$ was destroyed, transformation did not occur—the $\text{R}$ cells remained harmless.

• The Conclusion: The only substance whose destruction prevented transformation was $\text{DNA}$. They concluded that the "transforming principle"—the material responsible for genetic inheritance—was indeed Deoxyribonucleic Acid ($\text{DNA}$).

Avery's conclusion was initially met with skepticism by many scientists who still favored the more chemically complex proteins as the genetic material. However, the rigor of his chemical data proved overwhelming, and his work was conclusively supported by the 1952 Hershey-Chase experiment (Article 129), which used radioactive tracers to show that viruses inject $\text{DNA}$ (not protein) into bacteria to replicate.

The definitive identification of $\text{DNA}$ as the molecule of heredity opened the door for James Watson and Francis Crick's race to determine the structure of $\text{DNA}$ (Article 6), fundamentally launching the entire field of molecular biology.

In Conclusion: Frederick Griffith first demonstrated the existence of a "transforming principle" capable of transferring genetic traits between bacteria. Oswald Avery, Colin MacLeod, and Maclyn McCarty subsequently performed the definitive chemical experiments, systematically isolating the transforming substance and proving, by enzyme destruction, that Deoxyribonucleic Acid ($\text{DNA}$) is the molecule responsible for carrying genetic information. This discovery was the critical first step in defining the molecular basis of life.

In the early $20^\text{th}$ century, biologists knew that traits were inherited, but they did not know which chemical molecule carried this genetic information. The candidates were proteins (complex and abundant) and deoxyribonucleic acid ($\text{DNA}$), which was considered too simple to encode heredity. The critical shift in understanding began with the work of Frederick Griffith and culminated in the definitive experiments of Oswald Avery, proving that DNA is the ultimate molecule of inheritance, a discovery that paved the way for Watson and Crick's structural model (Article 6).

The British bacteriologist Frederick Griffith conducted experiments using two strains of the bacterium Streptococcus pneumoniae (which causes pneumonia in mice):

• S (Smooth) Strain: Virulent (deadly), protected by a polysaccharide capsule.

• R (Rough) Strain: Non-virulent (harmless), lacks the capsule.

Griffith performed four key injections on mice:

1. Live R Strain: Mouse lives. (Harmless)

2. Live S Strain: Mouse dies. (Deadly)

3. Heat-Killed S Strain: Mouse lives. (Deadly substance is destroyed)

4. Heat-Killed S Strain + Live R Strain: Mouse dies.

• The Shocking Result: From the dead mouse in the fourth group, Griffith recovered live S-strain bacteria. Somehow, the harmless $\text{R}$ bacteria had acquired the genetic trait (the ability to produce a capsule) from the dead $\text{S}$ bacteria.

• The Conclusion: Griffith proposed that a substance, which he called the "transforming principle," was transferred from the dead virulent cells to the live non-virulent cells, genetically changing (transforming) them. The chemical nature of this principle remained unknown.

Fifteen years later, at the Rockefeller Institute, Oswald Avery, Colin MacLeod, and Maclyn McCarty undertook the complex task of identifying Griffith's transforming principle.

• The Method: They took the heat-killed $\text{S}$ cells and used enzymes to systematically destroy one class of biomolecule at a time (proteins, $\text{RNA}$, $\text{DNA}$, lipids) before mixing the remnants with the live $\text{R}$ cells.

• The Critical Test: They used the enzyme DNase to destroy the $\text{DNA}$ in the $\text{S}$ cell extract. When the $\text{DNA}$ was destroyed, transformation did not occur—the $\text{R}$ cells remained harmless.

• The Conclusion: The only substance whose destruction prevented transformation was $\text{DNA}$. They concluded that the "transforming principle"—the material responsible for genetic inheritance—was indeed Deoxyribonucleic Acid ($\text{DNA}$).

Avery's conclusion was initially met with skepticism by many scientists who still favored the more chemically complex proteins as the genetic material. However, the rigor of his chemical data proved overwhelming, and his work was conclusively supported by the 1952 Hershey-Chase experiment (Article 129), which used radioactive tracers to show that viruses inject $\text{DNA}$ (not protein) into bacteria to replicate.

The definitive identification of $\text{DNA}$ as the molecule of heredity opened the door for James Watson and Francis Crick's race to determine the structure of $\text{DNA}$ (Article 6), fundamentally launching the entire field of molecular biology.

In Conclusion: Frederick Griffith first demonstrated the existence of a "transforming principle" capable of transferring genetic traits between bacteria. Oswald Avery, Colin MacLeod, and Maclyn McCarty subsequently performed the definitive chemical experiments, systematically isolating the transforming substance and proving, by enzyme destruction, that Deoxyribonucleic Acid ($\text{DNA}$) is the molecule responsible for carrying genetic information. This discovery was the critical first step in defining the molecular basis of life.