The Baby With No Ears.

 Part I – The Rise.

Post war Germany was teeming with anxiety. Utopia would come at a price. There was news of poverty, unemployment, and sleepless nights everywhere. The closing years of the war had been harsh and with the surprise aerial bombings from the Allied, the Germans only went to sleep at night unsure if they would wake up unscathed in the morning. As many testified, “drugs were used as a panacea to solve personal problems” and tranquilizers and barbiturate sedative use was at an all new high. In fact, accidental and deliberate overdosage led to many deaths. This was appropriate context for the heroic entry of our wonder drug “Thalidomide.”

Chemie Grunenthal was not a well-established corporation back in the day. The company had been family owned and had begun operations in Germany,1946. The company was the first to introduce penicillin to Germany in the post-war period. The Chief Scientist of Chemie Grunenthal was Dr Heinrich Muckter. Muckter had spent World War 2 (WW2) at an institution which tested drugs on Buchenwald concentration camp prisoners. He had a history of his own.

Grunenthal went on to introduce varied versions of many antibiotics in the market claiming either high efficacy or low side effects, but soon found the market to be saturated. In their search for a “wonder molecule,” the research team at the company stumbled upon α- phthaloylisoglutamine aka Thalidomide. What surprised the team was that you could take this drug at any amount whatsoever and it didn’t seem to cause any perceptible side effects. “In fact, the only thing that thalidomide seemed to have going for it was that “researchers could not find a dose high enough to kill a lab rat.”

One of the scientists at the company felt that the molecule shared structural similarities with barbiturates, a class of widely used sedatives, a fact disproved on multiple occasions in various trials much later. However, the hungry pharmaceutical company had finally landed their business opportunity. In a market heavily dependent on toxic, addictive sedatives, thalidomide, a non-toxic sedative would make them millions. “Thalidomide was introduced by the method of Russian roulette. Practically nothing was known about the drug at the time of marketing.”

 “Thalidomide was introduced by the method of Russian roulette. Practically nothing was known about the drug at the time of marketing.”

Source : Grunenthal research lan 1965 - Thalidomide tragedy 

 Back in the day there was no concept of human trials for drugs. The drug was marketed rampantly and free samples were distributed to doctors to popularize the drug. The drug gained a massive following, its hallmark quality being safety, and there were no prescriptions required. Thalidomide was promoted for anxiety, trouble sleeping, tension, and morning sickness in pregnant women. There were no studies against its use in pregnant women. They were even of the belief that drugs could not pass the placenta and effectively all drugs could safely be used in pregnancy. And so, it was consumed by all women during their pregnancy for severe symptoms of morning sickness. But then in the Christmas of 1956, a baby was born with no ears and it would all come crashing down hereafter.

Part II – The epidemic

Thalidomide, it was found, existed in 2 forms in nature. The R form and the S form. While R form was proven to be safe, it was the S form that seemed to cause teratogenic effects in mothers who consumed the drug. When researchers later tried to isolate the R form to elicit the sedative effects, they found that it rapidly interconverts to its S form thereby making an individual    enantiomer of no use to patients.

By this time, the drug had created enough hue and cry in the market. Thalidomide has been accepted globally in 46 nations and now each one of these countries were reporting severe birth defects. There was an epidemic of seal like babies who had other internal defects that caused large scale mortalities. The drug that had started being investigated on grounds of peripheral neuropathy in its consumers had now seen a large-scale shift in mortality and morbidity. In 1961 Dr William McBride, an Australian obstetrician, and Dr Widukind Lenz, a German pediatrician and geneticist, made independent observations linking thalidomide use in pregnancy to congenital malformations

Studies on the drug revealed that it had its maximum lethal effect during the days 20-36 after fertilization. This is scientifically regarded as the period of organogenesis in the fetus. This period coincidentally matched with the period of highest severity of morning sickness in most mothers causing them to take the drug at high doses. This was the perfect match, a disaster waiting to happen.

It was found that only a single 50mg tablet was enough to cause the birth defects. Shown below is a chronological display of the birth defects caused.

Source:  Neil Vargesson: Thalidomide Embryopathy: 

An Enigmatic Challenge. ISRN Developmental Biology Volume 2013, Article ID 241016, 18 pages

The most striking birth defects of course was Phocomelia, a Greek word that loosely translates to seal like flipper limbs. Phocomelia is a severe shortening of the limbs, where distal elements (hand plate) remains but proximal elements (long bones) are reduced or missing.

Embryologically, the radius/tibia and ulna/ fibula form in the developing limbs after the humerus/femur has begun to form. The digits of the hand/footplate are the last structures to form. Initially the structures form as cartilage condensations before ossifying into bone. This sequence of limb development offers some explanation as to why proximal structures are shortened or missing but distal structures are present in some thalidomide survivors.

"The most striking birth defects of course was Phocomelia, a Greek word that loosely translates to seal like flipper limbs. Phocomelia is a severe shortening of the limbs, where distal elements (hand plate) remains but proximal elements (long bones) are reduced or missing."

Source : Wikipedia

Source: Wikipedia

Due to its severe side effect profile, the drug was banned from the market in Europe in 1961. The United States had prevented this episode thanks to the untiring efforts of Dr. Frances Kelsey, a FDA reviewer who constantly found irregularities in the drug profile and prevented it from being introduced into the market, saving the healthcare a ton of resources and doing humanity a huge favor.

Part III – The Revival

Thalidomide appears to operate through anti-inflammatory and anti-angiogenesis mechanisms. As an anti-angiogenic drug, thalidomide inhibits tumor hypervascularity, growth, and metastasis. And so, due to these properties of thalidomide, it was reintroduced into the market for the treatment of leprosy and multiple myeloma. It also continues to be used for various solid organ cancers, inflammatory bowel disease, rheumatoid arthritis, Bechet’s disease and many other systemic inflammatory diseases. Thalidomide analogs like pomalidomide and lenalidomide have also been introduced.

However, today, The FDA has mandated a strict surveillance program to prevent the availability of thalidomide to pregnant women.

Source: Science Museum 

“The prime goal of clinical teratology is to identify and characterize environmental agents responsible for damage to the developing embryo, thus facilitating the removal of these agents from possible contact with the pregnant woman.”

Part IV – The Learnings

After the thalidomide saga, various laws were restructured and various new state laws were implemented by the FDA. Profound emphasis was laid on the process of informed consent, a procedure where the risks and benefits of each therapy or intervention taken on by a patient is explained in detail. At present, manufacturers must prove both effectiveness and safety of a new agent before it is authorized to be tested on humans. Today there is a mandate on transparency by drug manufacturing companies.

“The prime goal of clinical teratology is to identify and characterize environmental agents responsible for damage to the developing embryo, thus facilitating the removal of these agents from possible contact with the pregnant woman.”

It took 50 years for Grunenthal to finally issue an apology and compensate all the families that had been affected by this mass scale epidemic. Sadly, it will never truly be known how many women actually took the drug and faced the harsh consequences.

 

References:

1.       James H. Kim and Anthony R. Scialli (2011) Thalidomide: The Tragedy of Birth Defects and the Effective Treatment of Disease. TOXICOLOGICAL SCIENCES 122(1), 1–6 (2011)

2.       Neil Vargesson: Thalidomide Embryopathy: An Enigmatic Challenge. ISRN Developmental Biology Volume 2013, Article ID 241016, 18 pages

3.       Dark Remedy: The Impact of Thalidomide and Its Revival as a Vital Medicine;  Trent D. Stephens, Rock Brynner

4.       Wikipedia - Thalidomide