How one scientist averted a national health crisis

Dr Frances Oldham Kelsey : 20th-century American heroine for her role in the Thalidomide case

In 1960, Frances Kelsey was one of the Food and Drug Administration’s newest recruits. Before the year was out, she would begin a fight that would save thousands of lives — though no one knew it at the time.

  • Andrea Tone explains how Kelsey was able to prevent a massive national public health tragedy by privileging facts over opinions, and patience over shortcuts.
  • Video published on 7 June 2018 by TED-Ed.

Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray Syndrome

After 60 years, scientists uncover how thalidomide produced birth defects

More than 60 years after the drug thalidomide caused birth defects in thousands of children whose mothers took the drug while pregnant, scientists at Dana-Farber Cancer Institute have solved a mystery that has lingered ever since the dangers of the drug first became apparent: how did the drug produce such severe fetal harm?
ScienceAlert reports, 2 AUG 2018.

Abstract

Frequently used to treat morning sickness, the drug thalidomide led to the birth of thousands of children with severe birth defects. Despite their teratogenicity, thalidomide and related IMiD drugs are now a mainstay of cancer treatment, however, the molecular basis underlying the pleiotropic biology and characteristic birth defects remains unknown.

Here we show that IMiDs disrupt a broad transcriptional network through induced degradation of several C2H2 zinc finger transcription factors, including SALL4, a member of the spalt-like family of developmental transcription factors.

Strikingly, heterozygous loss of function mutations in SALL4 result in a human developmental condition that phenocopies thalidomide induced birth defects such as absence of thumbs, phocomelia, defects in ear and eye development, and congenital heart disease.

We find that thalidomide induces degradation of SALL4 exclusively in humans, primates and rabbits, but not in rodents or fish, providing a mechanistic link for the species-specific pathogenesis of thalidomide syndrome.

Thalidomide : The Drug that Came Back (in Brazil and in The UK)

Yorkshire Television, First Tuesday, 1993

Decades years after Thalidomide was launched, with devastating results, it was being hailed once again as a wonder drug.

Thalidomide is prescribed in Brazil, where there are a large number of leprosy patients, but children are still being born today in South America with limb defects because of its terrible effects in pregnancy.

Related Press Releases

  • 2011 – Thalidomide returns: scandal-hit drug is now used across NHS Independent.
  • 2004 – It’s backThe Guardian.
  • 1995 – The return of thalidomide Independent.

Why Dissent Matters

Because Some People See Things the Rest of Us Miss

The thalidomide tragedy was averted in the United States because Dr. Kelsey, alone and in the face of fierce opposition, did her job. Her perspective was educated, fresh and unique. If there had been no thalidomide crisis, the United States, with the rest of the world following, would still at some time have brought pharmaceutical regulation into the 20th century. But thalidomide created one of those moments when something had to be done. It could not be ignored in 1961-62, and it led immediately to a better and stronger regulatory system. Maybe someone else would have stopped thalidomide in the United States had Dr. Kelsey not been assigned the NDA, but, interestingly, no one else stopped it anywhere else until it was too late. Dr. Kelsey was the only person in the entire world who said no. She said no to a bad drug application, she said no to an overbearing pharmaceutical company and she said no to vested interests who put profits first. She was one brave dissenter. In the end, the question is not what made Frances Kelsey, but why aren’t there more like her?

Because Some People See Things the Rest of Us Miss

The nature writer Rachel Carson identified an emerging environmental disaster and pulled the fire alarm. Public protests, individual dissenters, judges, and juries can change the world – and they do.

A wide-ranging and provocative work on controversial subjects, Why Dissent Matters tells a story of dissent and dissenters – people who have been attacked, bullied, ostracized, jailed, and, sometimes when it is all over, celebrated.

William Kaplan shows that dissent is noisy, messy, inconvenient, and almost always time-consuming, but that suppressing it is usually a mistake – it’s bad for the dissenter but worse for the rest of us. Drawing attention to the voices behind international protests such as Occupy Wall Street and Boycott, Divest, and Sanction, he contends that we don’t have to do what dissenters want, but we should listen to what they say. Our problems are not going away. There will always be abuses of power to confront, wrongs to right, and new opportunities for dissenting voices to say, “Stop, listen to me.” Why Dissent Matters may well lead to a different and more just future.

Read This is Dr. Frances Kelsey’s story, the globe and mail, MAY 11, 2017.

Problems of Birth Defects

From Hippocrates to Thalidomide and After

From Hippocrates to thalidomide and after : original papers with commentaries by T.V.N. Persaud

A collection of 57 papers and commentaries, arranged in eight sections, discuss the historical aspects, epidemiology, mechanisms, genetics, etiology, prenatal diagnosis, management, and social aspects of birth defects.

  • Paperback: 399 pages
  • Publisher: University Park Press (1977).
  1. Beliefs, Mythology, Magic and Superstition.
    • Congenital malformations in the past.
    • A brief history of teratology to the early 20th century.
  2. Epidemiology of Birth Defects.
    • Classification and nomenclature of morphological defects.
    • Epidemiologic aspects of the problem of congenital malformations.
    • Congenital malformations. A report of a study of series of consecutive births in 24 centres. (Extracts).
    • The incidence of developmental and other genetic abnormalities.
  3. Teratological Mechanisms.
    • Interrelation of the common congenital malformations. Some aetiological implications.
    • Defective regulatory mechanisms in teratogenesis.
    • Mechanisms of teratogenesis.
    • Congenital postural deformities: perinatal associations.
  4. Cytogenetic and Chromosomal Studies.
    • A morphological distinction between neurones of the male and female, and the behaviour of the nucleolar satellite during accelerated nucleoprotein synthesis.
    • The detection of chromosomal sex in hermaphrodites from a skin biopsy.
    • The chromosome number of man.
    • Retrospective and prospective epidemiological studies of 1500 karyotyped spontaneous human abortions.
    • Chromosome abnormality and perinatal death.
    • Cytogenetics of fetal wastage.
    • Spontaneous abortion and aging of human ova and spermatozoa.
    • Where have all the conceptions gone?
    • Genetics of common disorders.
    • Genetic hazards to man from environmental agents.
  5. Environmental Influences and Congenital Abnormalities.
    • Pigs born without eye balls.
    • Congenital cataract following German measles in the mother.
    • The role of viruses in congenital defects.
    • Congenital toxoplasmosis. A prospective study of 378 pregnancies.
    • Therapeutic abortions with a folic acid antagonist, 4-aminopteroyl-glutamic acid (4-amino P.G.A.) administered by the oral route. (Extract).
    • Diskussionsbemerkung von Privatdozent Dr. W. Lenz, Hamburg, zu dem Vortrag von R. A. Pfeiffer und K. Kosenow: Zur Frage der exogenen Entstehung schwerer Extremitatenmissbildungen.
    • Thalidomide and congenital abnormalities.
    • Foetal malformations due to thalidomide.
    • Nonadrenal female pseudohermaphrodism after administration of testosterone to mother during pregnancy.
    • Masculinization of female fetus due to use of orally given progestins.-
    • Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women.
    • Are anti-epileptics harmful in pregnancy? (Extract).
    • Anticonvulsant drugs and congenital abnormalities.
    • Congenital abnormalities and anticonvulsant drugs.
    • A clinical look at the problem of drugs in pregnancy and their effect on the fetus.
    • Intra-uterine methylmercury poisoning in Iraq.
    • Assessing the impact of low level chemicals on development: behavioral and latent effects.
    • A preliminary report of cigarette smoking and the incidence of prematurity. (Extract).
    • Effect of mothers’ smoking habits on birth weight of their children.
    • The fetal alcohol syndrome.
    • Potatoes and spina bifida.
    • The outcome of 625 pregnancies in women subjected to pelvic radium or roentgen irradiation. (Extract).
    • Radiation and pregnancy.
  6. Detection of Environmental Teratogens.
    • Environmental factors in the etiology of human malformations: perspectives and problems of evaluation.
    • Hazards of the first nine months: an epidemiologist’s nightmare.
  7. Prenatal Diagnosis and Management of Congenital Abnormalities.
    • Prenatal diagnosis of genetic disorders. An analysis of experience with 600 cases.
    • Prenatal diagnosis of mongolism by X-ray.
    • Diagnosis of congenital fetal abnormalities by sonography.
    • Amniography for detection of congenital malformations.
    • Diagnosis of human fetal abnormalities by fetography.
    • Genetic counselling-or what can we tell parents?.
    • Pre-, peri- and postnatal prevention of major neuropediatric handicaps.
  8. Social, Ethical, and Medico-Legal Problems.
    • Moral and ethical problems of pre-natal diagnosis.
    • Attitudes toward defective newborns.
    • Ethical and social aspects of treatment of spina bifida.
    • Moral and ethical dilemmas in the special-care nursery.
    • Further References.
More DES DiEthylStilbestrol Resources

Time Bomb: a Journey into Old Exposures, Gametic Glitches, and the Autism Explosion

Slides from Society for Neuroscience Wonder, February 2017

This presentation to a student-run chapter of SFN explained the history and science behind the “Time Bomb” hypothesis of autism.

DES DiEthylStilbestrol Resources

Out of the Past

Old Exposures, Heritable Effects, and Emerging Concepts for Autism Research

The presentation highlights a significant gap in autism research: what factors might be driving the heterogenous de novo genomic errors seen in autism?

Sources:
More DES DiEthylStilbestrol Resources

A snapshot of the thalidomide tragedy

An infographic via “The Conversation”

infographic snapshot-of-the-thalidomide
The Conversation is an independent news and commentary website produced by academics and journalists. Free to read and republish.
Health infographics
Related posts

Dr Frances Oldham Kelsey: 20th-century American heroine for her role in the Thalidomide case

Frances Oldham Kelsey, F.D.A. stickler who saved U.S. babies from Thalidomide, dies at 101

Dr-Frances-Oldham-Kelsey
Dr Frances Oldham Kelsey, the Canadian doctor who played a central role in preventing the drug thalidomide being distributed in the US, has died at 101. Image of Kelsey with President John F. Kennedy signing the 1962 Drug Amendments (FDA051) by the The U.S. Food and Drug Administration.

A Londoner who’s kept the scourge of thalidomide out of the United States has died, leaving behind a legacy of achievement that made her a heroine south of the border.

In 1962, President John F. Kennedy awarded Kelsey the highest honour given to a civilian in the U.S., the President’s Award for Distinguished Federal Civilian Service. Kelsey was only the second woman to receive the award. The new laws would pass and Kelsey would play a leading role giving them force.

Dr Frances Kelsey spent her final years here with family after a trail-blazing career that once led the Baltimore Post-Examiner to call her America’s greatest living heroine.

Sources and more information
  • Frances Oldham Kelsey, F.D.A. Stickler Who Saved U.S. Babies From Thalidomide,
    Dies at 101
    , NYtimes, AUG. 7, 2015.
  • Frances Oldham Kelsey – a true American hero turns 100,
    Baltimore Post-Examiner, July 26, 2014.
  • America’s Greatest Living Heroine Frances Oldham Kelsey – 98 and forgotten,
    Baltimore Post-Examiner, February 11, 2013.
  • Thalidomide and the 1962 Kefauver-Harris Drug Amendments, FDA.
  • About the life and work of Dr. Kelsey: Autobiographical Reflections, FDA.

Thalidomide: how men who blighted lives of thousands evaded justice

Documents raise fresh questions about thalidomide criminal trial

Harold Evans cartoon image
Sir Harold Evans’ paper is about newly exposed files showing how victims were betrayed by political interference in trial – and how the pill has remained on sale .

The dark shadow of thalidomide is still with us. The original catastrophe maimed 20,000 babies and killed 80,000… …Now evidence has been uncovered that the pharmaceutical outrage was compounded by a judicial scandal that has suppurated all these years.

Documents recently unearthed by the UK’s Thalidomide Trust will surely stoke fresh controversy about how and why the criminal trial against the drug’s makers ended without a verdict in December 1970.

And more than half a century since the pill’s threat to an embryo was proven, the company that produced the first disaster has continued to sell the drug in parts of Latin America. ”