Teaser Appetizer: Not so Nobel

You have been selected to the jury to award the Nobel Prize (NP) in medicine. One of the contenders for the prize is the multiple antiviral drug therapy for HIV-AIDS. Surely, you say, this therapy has prolonged the lives of millions of HIV patients who were otherwise doomed, which makes it a favorite in your mind. But then you consider that it does not guarantee cure; while it is a great innovation it is not a fundamental discovery. How do you decide? Let us look at the history of Nobel Prizes in physiology or medicine.

The Nobel Prize (NP) has propelled brilliant scholars into the stratosphere of fame; many scientists have flown high and long on the wings of a seminal discovery but a few have glided back to ground in a short time. Only rarely has there been an unceremonious crash.

One hundred and five years ago, on 10 Dec 1901, Emil Behring [photo on right] won the first Nobel Prize in medicine for his work on the serum therapy of diphtheria. Nobel has since then honored one hundred eighty five more scientists in physiology or medicine. The annual continuity of the Nobel Prize (NP) suffered interruption during the world wars, so the prize has been awarded only ninety eight times.

Not all Nobel are equal. That arbitrary quintessential American measure of everything – small, medium and large – could well describe the durability and the impact of the Nobel discoveries. Durability signifies longevity of the validity of the discovery before its improved replacement arrives and impact shows the breadth of humanity that it benefits.

Ninety-one such discoveries out of a total of ninety-eight “Large impact” discoveries have opened gates to new vistas and have changed our lives forever, without us being so aware. The list is impressive and includes normal biological functions, pathogenesis of disease, tools of investigation and therapeutics.

The honor of the “Triple-extra-large impact” and arguably the largest impact discovery belongs to deciphering the very code of life that lay curled up -- smug and self-assured -- for over 3.5 billion years. For unraveling the twists of DNA, Francis Crick, James Watson and Maurice Wilkins received the NP 1962.

Some “large” discoveries have helped us:

• Quantify molecules, hitherto immeasurable (radio-immune assay: Yallow, 1977)
• Pierce the crevices of body but without a knife (CAT: Cormack and Hounsfield 1979; MRI: Lauterbur and Mansfield 2003)
• Indict the culprits (Tuberculosis: Koch 1905; Prions: Prusiner 1997)
• Understand mundane functions (Olfactory system: Axel and Buck 2004; dioptrics of the eye: Gullstrand 1911)

The large Nobel has a long life. The very second NP was awarded to Ross in 1902 for the discovery of the pathogenesis of malaria and the lifecycle of the malarial parasite. His work is still valid more than a century later.

But there also have been discoveries with a shorter life span. Five such “Medium impact” discoveries have provided extraordinary windows of opportunity. They may not have been durable but they have ushered subsequent important discoveries:

• 1903: Niels Finsen treated tuberculosis of the skin with concentrated sunlight and founded the Finsen Institute of Photo-therapy in Copenhagen in 1896. Antibiotics have replaced sunlight but this notion perhaps continues remotely with radiation treatment of cancer.
• 1926: Johanes Fibiger induced first experimental cancer in rat stomachs (Spiroptera carcinoma) by feeding them cockroaches infected with a worm called Gongylonema neoplasticum. Subsequently coal tar application produced skin cancer in other animal experiments. His mentors Koch and Behring also won Nobel for other discoveries.
• 1934:George Whipple, George Minot and William Murphy got the NP for their discoveries in treating pernicious anemia with liver extracts. Currently we treat pernicious anemia with vitamin B12.
• 1939:Gerhard Domagk proved the antibacterial effects of prontosil rubrum (red dye - a derivative of sulfanilamide), which paved the way for the development of sulfonamide dugs. He proved the efficacy of prontosil in mice and rabbits infected with staphylococci and streptococci. It so happened that his daughter fell deathly sick with streptococcal infection and he administered one dose of prontosil with skepticism -- and in desperation. She recovered completely. Later he conducted wider successful human trials.
• 1948: Paul Muller discovered the efficacy of DDT as a poison against arthropods. DDT was the main weapon in many countries for the control of mosquitoes causing malaria three decades ago but it went into disrepute when suspicions mounted for its toxic effect on humans and wild life. But recently on 15 Sept 06, the WHO has unambiguously rehabilitated this insecticide by recommending indoor spraying of the walls and roofs of the houses to kill malaria laden mosquitoes. Data has confirmed its safety in both humans and animals.

The ‘Oscar’ for the story, however, goes to two “Small impact” NP discoveries that have been peepshows of transient excitement and probably did more harm than good. These two Nobel discoveries stand out as not so noble. A fortuitous meeting of three scientists in a neurology conference in London set the stage for the first tragic discovery. The scientists were Fulton, Moniz and Freeman.

Fulton, like other scientists before him, had demonstrated that frontal lobotomy calmed the Chimpanzees. He shared this observation with Moniz, a Portuguese doctor, who mulled over this experimental idea and argued that cutting the nerve fibers between the frontal cortex and the thalamus (frontal leucotomy) could benefit psychotic patients with incurable hallucinations and obsessive-compulsive ideas. He would insert an ice pick like instrument on each side of the brain and with a few sweeps damage part of the frontal cortex. Some patients became docile but many deteriorated.

In 1936 Freeman and his coworker refined the lobotomy procedure and named it “Freeman-Watts Standard Procedure.” The pair demonstrated the procedure in the USA and made it extremely popular. Thus started the lobotomy craze. But further serious observation revealed that lobotomy harmed two thirds of patients and barely benefited the rest. What Fulton had investigated in animals, Freeman popularized in humans. But it was Antonio Egas Moniz [photo on right] who received the honor of the NP in 1949.

Unfortunately, he also received a bullet in his back from one of his not-so-happy patients a few years later, which left him paraplegic for life. His physical immobility ironically mirrored the emotional paralysis of some frontal lobotomy patients.

If this “small impact” NP was a consequence of a chance meeting of scientists the second “small impact” NP discovery resulted from serendipity.

When Wagner-Jauregg, like other investigators before him, observed that some patients with neuro-syphilitic paresis, improved after a febrile illness like typhoid or erysipelas, he set out to induce experimental febrile illness in his patients with a series of toxins. In 1888 he infected several patients with injections of streptococci. Stung by criticism, in 1890 he switched to non-infectious tuberculin; then in 1902 he used sodium nulleinate, boiled milk and milk protein - all in an attempt to induce fever. A few years later he observed a soldier suffering from neurosyphilis had improved with concomitant malaria. So in 1917 he started infecting syphilitic paretic patients with malaria.

War had probably blunted his sensitivity and he juxtaposed his treatment against the insane cruelty of war. He observed, “ We were already in the third year of the war, and its emotional implications became more manifest from day to day. Against such a background, a therapeutic experiment could stir me little, in particular since its success could not be foreseen. What meant a few paralytics, would possibly be saved, in comparison to the thousands of able-bodies and capable men who often died on a single day as the result of the prolongation of the war.”

The success of the treatment silenced its critics except one member of the prize committee: Dr Gadelius, a Swedish psychiatrist objected to giving the Nobel Prize because he thought a physician who injected malaria into a patient with advanced syphilis was a ‘criminal.’ Notwithstanding this dissent, Julius Wagner-Jauregg [photo on right] received the NP in 1927 for demonstrating therapeutic benefits of malaria in syphilitic dementia and paralysis. Many hailed this as a “therapeutic noble deed” for a hopeless condition.

The story of small impact NP exemplifies the pitfall of any discovery. While all Nobel Laureates shine brightly in the limelight, yet on some the lights dim before the fifteen minutes of fame expire. Some migrate into cache of history and others disappear into the recycle bin but none gets deleted.

Does this brief background help you in deciding if the antiviral cocktail therapy for HIV-AIDS deserves the prize? Well, you should also know that some NP winning therapeutic interventions belong to “medium or small impact” categories. You say, in that case an HIV vaccine - when available - will be more deserving.

But no vaccine has ever won the prize.

So you go ahead and vote. The Nobel jury does not have to be perfect; science, unlike religion, is fallible.