The Five Pioneers Who Transformed Our Understanding of the Disease
In 2004, an exceptional group of scientists stood on stage in Oviedo, Spain, to receive one of the world's most prestigious scientific honors: the Prince of Asturias Award for Technical and Scientific Research. The recipients—Judah Folkman, Tony Hunter, Joan Massagué, Bert Vogelstein, and Robert Weinberg—represented the vanguard of cancer research, each having cracked open fundamental mysteries of how cancer begins, grows, and spreads 1 7 .
At the time of the award, cancer biology was experiencing a golden age of discovery, and these scientists were at its forefront. Their work exemplified what the Jury called "the noblest side of science" 3 .
Before the work of these award-winning scientists, cancer was often viewed as a mysterious and implacable foe. Their research helped transform our understanding from a purely clinical description to a molecular one.
Robert Weinberg pioneered the genetic understanding of cancer, making the landmark discoveries of the first human oncogene and the first tumor suppressor gene 1 . His work identified specific drivers like the ras oncogene and the rb tumor suppressor gene, providing crucial evidence that cancer is fundamentally a genetic disease 5 .
Judah Folkman, often called the father of angiogenesis, proposed a then-revolutionary theory that tumors cannot grow beyond a tiny size without developing their own blood supply. He discovered that tumors recruit and create new blood vessels through a process called angiogenesis 5 .
Tony Hunter made a pivotal discovery in 1979 when he identified a new mechanism cells use to control growth. He found that certain enzymes, called tyrosine kinases, add phosphate groups to the amino acid tyrosine on proteins, acting as a crucial "on" switch for cell division 5 .
Joan Massagué has dedicated his career to understanding the complex signals that control cell division and cancer spread. His work has focused extensively on TGF-beta, a factor that can normally inhibit cell proliferation but can also paradoxically promote metastasis 9 .
Bert Vogelstein meticulously mapped the precise sequence of genetic mutations that lead to colon cancer, providing one of the first complete pictures of how a normal cell evolves into a cancerous one. His work identified key genes like APC and clarified the role of the crucial p53 tumor suppressor gene 5 .
| Scientist | Key Discovery | Impact on Cancer Research |
|---|---|---|
| Robert Weinberg | First human oncogene & first tumor suppressor gene | Established genetic basis of cancer; identified specific drivers like ras and rb 1 5 |
| Judah Folkman | Tumor angiogenesis (blood vessel growth) | Revealed tumors need a blood supply; opened field of anti-angiogenesis therapy 5 |
| Tony Hunter | Tyrosine phosphorylation | Uncovered key "on" switch for cell growth; enabled targeted drug development 5 |
| Joan Massagué | TGF-beta pathway in growth inhibition & metastasis | Elucidated how cancer cells spread; identified key inhibitors like p27 5 9 |
| Bert Vogelstein | Genetic sequence of colon cancer (e.g., APC, p53) | Provided a model for cancer evolution; identified critical mutations in specific cancers 5 |
While many discoveries contributed to the 2004 award, Tony Hunter's 1979 investigation into protein phosphorylation stands as a classic example of a foundational experiment that opened an entirely new field of inquiry.
Hunter suspected that a virus (v-src) known to cause cancer might do so by altering the phosphorylation state of proteins in infected cells.
Hunter grew cells infected with the Rous Sarcoma Virus in a medium containing radioactive phosphate (³²P). This allowed him to track where phosphate groups were being added to cellular proteins.
He extracted proteins and used electrophoresis to separate them, resulting in an autoradiograph showing specific protein bands that had incorporated the radioactive phosphate.
The critical, innovative step: Hunter cut out radioactive protein bands and subjected them to strong acid hydrolysis, breaking down proteins into individual amino acids.
He separated amino acids using a two-dimensional technique. To his surprise, he found a distinct radioactive spot that did not correspond to any known phosphorylated amino acid.
Through further chemical analysis, Hunter definitively identified this unknown spot as phosphotyrosine. This proved that the v-src oncogene was encoding an enzyme that specifically attached phosphate groups to tyrosine residues 5 .
The core result was the discovery of a new biochemical reaction: tyrosine phosphorylation. This single finding had profound scientific importance:
It revealed a previously unknown mechanism of cellular regulation, fundamentally expanding the understanding of signal transduction.
It explained how certain oncogenes hijack normal cellular processes by constantly sending "grow" signals.
It opened the door for the discovery of many more tyrosine kinases, enabling targeted drug development 5 .
| Experimental Step | Procedure | Outcome |
|---|---|---|
| 1. Induce Phosphorylation | Infect cells with Rous Sarcoma Virus (v-src) in ³²P medium | Cellular proteins in infected cells become radioactively labeled |
| 2. Separate Proteins | Electrophoresis of cell extracts | Autoradiograph reveals specific phosphorylated protein bands |
| 3. Break Down Proteins | Acid hydrolysis of isolated protein bands | Proteins are broken down into individual amino acids |
| 4. Identify Phospho-Amino Acids | 2D separation (electrophoresis + chromatography) | Detection of an unknown phosphorylated amino acid |
| 5. Discovery | Chemical analysis of the unknown spot | Identification of phosphotyrosine |
Impact: The knowledge of tyrosine kinases has been determinative for the development of a new generation of drugs in the treatment against oncological diseases. Drugs like imatinib (Gleevec), which specifically inhibits a faulty tyrosine kinase that causes chronic myeloid leukemia, are direct descendants of Hunter's foundational work 5 .
Essential Research Reagents in Cancer Biology
The breakthroughs made by these researchers were made possible by a suite of specialized reagents and tools. Below are some of the essential components of the molecular oncologist's toolkit.
| Research Reagent / Tool | Function in Cancer Research | Example of Use |
|---|---|---|
| Signer DNA | Exceptionally pure DNA samples used in structural studies | Used by Maurice Wilkins and Raymond Gosling for X-ray diffraction, which was foundational for understanding genetic material 4 |
| Phospho-specific Antibodies | Antibodies that bind only to a protein phosphorylated at a specific site (e.g., on tyrosine) | Allows researchers to detect and measure active tyrosine kinases in cancer cells, building on Hunter's discovery 5 |
| TGF-beta | A cytokine (signaling protein) that can inhibit cell proliferation or promote metastasis | Used by Joan Massagué and others to study the dual role of this factor in cancer progression and suppression 5 9 |
| Recombinant Angiogenic Factors | Purified proteins like VEGF that stimulate blood vessel growth | Used to test Folkman's angiogenesis theory and to screen for potential anti-angiogenesis drugs 5 |
| Cell Lines with Engineered Oncogenes | Cultured cells genetically modified to express specific cancer genes | Allow researchers like Weinberg and Vogelstein to study the effect of a single oncogene or mutated tumor suppressor in isolation 1 5 |
The fundamental research conducted by Folkman, Hunter, Massagué, Vogelstein, and Weinberg was never purely an academic exercise. Its true value lies in its translation into tangible benefits for patients.
The understanding of tyrosine kinases led directly to a new generation of targeted therapies 5 . Drugs like imatinib (Gleevec) and gefitinib (Iressa) are designed to specifically block the activity of mutant tyrosine kinases that drive certain leukemias and lung cancers.
Folkman's theory of angiogenesis faced initial skepticism but ultimately gave rise to a legacy of anti-angiogenic drugs such as bevacizumab (Avastin), which starves tumors by targeting the vascular endothelial growth factor (VEGF) 5 .
Meanwhile, Massagué's ongoing research into the "molecular signature" of metastasis aims to answer one of oncology's most pressing questions: why and how do some cancer cells spread? The answers could lead to therapies that prevent cancer from becoming lethal 9 .
When the Prince of Asturias Award was granted in 2004, the Jury specifically acknowledged not only the five laureates but also "the efforts of so many scientists throughout the world in their struggle to prevent and treat cancer," framing it as "a time of hope for oncogene research" 3 .
The award to these five scientists celebrated a paradigm shift—a move from seeing cancer as an untreatable scourge to understanding it as a set of molecular problems that can be dissected, understood, and ultimately solved.
The story of these five researchers underscores a central truth of modern science: that progress against humanity's most complex challenges is built on collaboration, international cooperation, and the long-term pursuit of fundamental knowledge. Their collective work, recognized nearly two decades ago, continues to inspire and inform the development of life-saving therapies today, proving that investing in basic science is one of the most powerful ways to invest in human health.