Did you know a crucial finding was discovered then ignored for nearly a century in treating sickle cell disease?

1927 experiment by William Hahn and Elizabeth Gillespie showing that low oxygen (deoxygenation) triggers sickling of red blood cells.

Key study

• William Hahn and Elizabeth Gillespie (1927)

   

• Demonstrated that removing oxygen from blood samples caused red cells from sickle cell patients to become sickle-shaped, while restoring oxygen reversed the shape change.

   

What they actually did

• They observed that distorted sickle cells could return to normal shape when oxygen was present.

   

• They then exposed blood to gases without oxygen (or high CO₂).

   

• Under those low-oxygen conditions, the red cells consistently sickled.

   

This experiment established a foundational principle of sickle cell pathophysiology:

Deoxygenation → hemoglobin S polymerization → red cell sickling.

How it’s usually cited

Most textbooks reference it as:

Hahn, W. and Gillespie, E.B. (1927).
“Sickling of red blood cells in relation to oxygen tension.”
Archives of Internal Medicine.

(Some sources list the title slightly differently, but it’s the same 1927 Arch. Internal Medicine paper.)

Why the study mattered

Their work was the first clear demonstration that oxygen tension controls sickling, which later led to the understanding that:

• Deoxygenated hemoglobin S polymerizes

   

• This polymerization distorts the red blood cell into the sickle shape

   

• Re-oxygenation can temporarily reverse the shape.

   

Citation

• J. B. Scriver

   

• T. R. Waugh

   

• Canadian Medical Association Journal, 1930, 23(3): 375–380.

   

What the study showed

Scriver and Waugh demonstrated that initial sickling of red blood cells is reversible and depends on oxygen tension. They reported that:

• The percentage of sickled cells increases when oxygen pressure falls.

   

• Sickling occurs when oxygen tension drops to ~45 mm Hg.

   

• Re-oxygenation allows many cells to return to their normal discoid shape, showing the process is reversible in early stages.

   

Their experiment

They performed an in-vivo hypoxia experiment by:

• Placing a rubber band around a patient’s finger to create venous stasis (reducing oxygen supply).

   

• Observing that sickled cells increased dramatically—from about 15% to over 95% in the stagnant blood.

   

Why this paper mattered

Together with the earlier 1927 work of
William E. Hahn and
Elizabeth B. Gillespie,

the Scriver & Waugh study helped establish the core principle of sickle cell physiology:

Low oxygen → sickling occurs → re-oxygenation can reverse early sickling.

linical trial by Alvin Zipursky and colleagues that evaluated oxygen therapy during sickle cell crises.

Study

Oxygen Therapy in Sickle Cell Disease

• Authors: Alvin Zipursky, Isabelle Robieux, Elizabeth Brown, Hugh O’Brodovich, Nancy Olivieri, et al.

   

• Journal: American Journal of Pediatric Hematology/Oncology

   

• Year: 1992 (randomized clinical trial)

   

What the study did

Researchers studied patients with sickle cell disease and:

• Gave 50% oxygen by mask to some patients

   

• Compared them with patients receiving room air

   

• Measured reversibly sickled cells (RSCs) and irreversibly sickled cells (ISCs) during crisis.

   

Key finding relevant to your question

• Oxygen reduced reversibly sickled cells somewhat.

   

• But it did not reduce irreversibly sickled cells once they were present.

   

• Most importantly, oxygen therapy did not shorten the duration of the pain crisis or hospitalization.

   

Why this led to the idea that hospital oxygen may be “too late”

By the time patients arrive at the hospital:

• Many cells are already irreversibly sickled (ISC).

   

• These cells cannot return to normal shape even with oxygen.

   

• They must instead be cleared by hemolysis or the spleen, which can take days to weeks.

   

So the implication drawn from the trial was:

Once a vaso-occlusive crisis is established, oxygen alone cannot reverse the process — the sickling damage has already occurred.

Simple timeline connecting the classic studies

1. William Hahn & Elizabeth Gillespie (1927) – low oxygen causes sickling.

    

2. J. B. Scriver & T. R. Waugh (1930) – early sickling is reversible with oxygen.

    

3. Alvin Zipursky (1992) – in established crisis, oxygen therapy does not change clinical outcomes, suggesting intervention may be too late once irreversible sickling dominates.

Ming Dao, Suresh Suresh, and collaborators demonstrating sickle cells under changing oxygen levels in a microfluidic device.

MIT: Modeling Sickle Cell Behavior with Controlled Oxygen Levels

What the MIT video shows

In this experiment:

• Blood from a sickle cell patient flows through a microfluidic channel.
• Researchers lower the oxygen level to simulate conditions in small blood vessels.
• The red blood cells change from normal discs to sickle shapes.
• When oxygen is restored, many cells return to their normal discoid shape.

This visually demonstrates the classic principle discovered in earlier research:

• Deoxygenation → sickling
• Re-oxygenation → restoration of reversible sickle cells

The MIT footage is often used in lectures because you can literally watch the cells sickle and then “unsickle” when oxygen returns. The images show sickled cells on the low-oxygen side and normal cells again once oxygen is reintroduced.

Why the video is important

It provides real-time visual proof of the reversible phase of sickling that earlier studies described:

• William Hahn & Elizabeth Gillespie (1927) – low oxygen triggers sickling
• J. B. Scriver & T. R. Waugh (1930) – early sickling is reversible
• MIT microfluidic experiment (2015) – visually demonstrates the reversible process at the cellular level.

A key takeaway from the MIT demonstration

Researchers showed that when oxygen is restored quickly, many sickled cells regain their normal shape and flow more easily again.

Key paper

“Sickle Cell Crisis – Home Oxygen in the Golden Half Hour”
Published in Medical Hypotheses / ScienceDirect (recent literature review and hypothesis paper).

Main point of the study:

• Early sickling is reversible if oxygen is restored quickly.

   

• The paper describes a “golden half hour” (~30 minutes) where oxygenation can restore cells before permanent membrane damage occurs.

   

• It states that reoxygenation during this early window can return reversible sickle cells to their normal discoid shape before they become irreversible sickle cells.

   

What the study explains

• Reversible sickle cells (RSC): can return to normal shape when oxygen is restored.

   

• Irreversible sickle cells (ISC): membrane damage prevents them from recovering even with oxygen.

   

• The transition from RSC → ISC is time-dependent.

   

• If oxygen is restored within roughly the first 30 minutes, many cells can still recover their normal shape.

   

How this fits with earlier research

The 30-minute concept builds on earlier foundational studies:

• 1927 – William Hahn & Elizabeth Gillespie
  Low oxygen causes sickling.

   

• 1930 – J. B. Scriver & T. R. Waugh
  Early sickling is reversible with re-oxygenation.

   

• 1992 – Alvin Zipursky clinical trial
  Oxygen reduces reversibly sickled cells, but once a crisis is established many cells are already irreversibly sickled.

   

Key physiological idea

The mechanism is time-dependent hemoglobin S polymerization:

1. Low oxygen → HbS polymerization → sickle shape

    

2. Short exposure → reversible

    

3. Prolonged exposure → membrane damage → irreversible sickle cells

    

Did you know…?

Sickle cell red blood cells don’t start out permanently damaged.

For a critical window of time, they are reversible.

In 1927 William Hahn and Elizabeth Gillespie discovered that low oxygen causes red blood cells to sickle—and restoring oxygen can return them to normal shape.

Just a few years later in 1930, J. B. Scriver and T. R. Waugh demonstrated that early sickling is reversible with re-oxygenation. Timing is everything…oxygen given within 30 minutes was the key discovery.

But here’s the problem…

By the time many patients reach the hospital during a pain crisis, a significant number of cells have already become irreversibly sickled—meaning oxygen can no longer help them.

This was reflected decades later in clinical work by Alvin Zipursky, where oxygen given in the hospital did not significantly change outcomes during established crises.

So what if we’re intervening too late?

What if we shifted our focus from reactive care… to early intervention?