300: How My Mom Discovered A Cure For A Rare Disease

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Gene therapy for glycogen storage disease works by delivering a functional copy of the glucose-6-phosphatase gene into the liver using a viral vector, replacing the enzyme patients cannot produce. My mom, Janice Chou, cloned that gene at the National Institutes of Health after 50 years in which nobody had managed it, and the therapy built on her vector is now in clinical trials.

For episode 300 I wanted a guest who had done something genuinely extraordinary. My mom is a molecular biologist at NIH, and I spent chunks of my childhood in her lab playing with dry ice and liquid nitrogen.

This episode covers how she got from fleeing Shanghai to a PhD in Utah to a permanent lab at NIH, how the gene discovery actually happened, and her advice for anyone who wants to do this kind of work.

Key takeaways

• Glycogen storage disease type 1a affects about 1 in 100,000 people and prevents converting glycogen into glucose.
• The gene resisted cloning for 50 years because the protein is fat soluble and cannot be dissolved in water.
• She found it by accident, while isolating genes differentially expressed in a hypoglycemic mouse model.
• The existing treatment is raw cornstarch every four to six hours, including waking up overnight.
• Around 90% of an injected viral vector goes to the liver, which makes liver diseases the easiest gene therapy targets.
• Most patients in the trial no longer needed cornstarch and could sleep through the night.
• Her career advice is focus. One or two projects done deeply beats ten done shallowly.
• She developed roughly 80% of the reagents used in her own research because commercial versions did not work.

How Janice Chou got from Shanghai to a PhD in Utah

Her family fled Shanghai for Taiwan during the Communist Revolution, leaving their wealth behind. Her father worked in government, which kept the family middle class enough to send children to college.

She was strong in math, chemistry, and biology and weak in literature and history, so science was the obvious track when Taiwanese high schools split students into science and humanities.

Her grades were good enough to skip the college entrance exam entirely, and she studied pharmacy at Taiwan University.

Advanced degrees required going abroad, since Taiwan had no graduate programs at the time. She also had a practical reason to skip pharmacy practice, since Taiwanese pharmacies and medicine were largely controlled by native Taiwanese and she was from mainland China.

Her choice of school was less rigorous than her science. She looked at a map of America, decided against Harvard as probably too difficult, wanted a large state, and put her pen on Utah.

She earned a fellowship, got her PhD in biochemistry at the University of Utah, and met my dad in the library there.

How she got a permanent lab at NIH

Her professor at Utah connected her to someone at NIH when my dad took a job in Maryland.

The contact had left long ago. She asked to speak to anyone else in the department, visited, and one doctor introduced her to Dr. Maxine Singer.

By the time she flew back to Utah, an acceptance letter was already on her desk.

Six years of postdoctoral training followed, first learning molecular biology and biochemistry under Singer, then virology under Dr. Martin. She published eight strong papers in her first postdoc, which is unusual.

She then became a unit head at NIH, a temporary position rather than a permanent one.

The permanent job came from leverage. Georgetown University was looking for a woman virologist, she interviewed and was offered the position immediately, and NIH responded by making her permanent in 1983. She never intended to take the Georgetown job.

What glycogen storage disease type 1a does

Between meals, your body converts stored glycogen into glucose, which is why you can go hours without eating.

Patients with this disease cannot make that conversion. The pathway stops at glucose-6-phosphate, the compound immediately before glucose.

The consequence is hypoglycemia and seizures, and without prompt treatment it can be fatal.

It is genuinely rare, affecting roughly one in 100,000 people.

How cornstarch therapy keeps patients alive

Before the gene was cloned, Thomas Kingsford discovered dietary therapy using raw cornstarch.

Cornstarch digests slowly into glucose, which buys patients four to six hours without food.

That means waking up at least once every night to take more cornstarch.

It works well enough that patients survive, grow up, and go to college, and it is a permanent schedule with no days off.

Why the glucose-6-phosphatase gene resisted cloning for 50 years

Glucose-6-phosphatase deficiency was known to cause the disease for many years before anyone could work with the gene.

The obstacle was solubility. The protein is highly fat soluble and cannot dissolve in water, so it could never be purified, sequenced, or characterized.

That also ruled out the obvious treatment. Enzyme replacement therapy requires a purified functional enzyme, and nobody could produce one.

How the discovery actually happened

My mom was studying liver gene regulation, looking for genes differentially expressed in a hypoglycemic mouse model. Cloning glucose-6-phosphatase was never the goal.

They isolated a batch of genes and sequenced them, and one turned out to be strikingly fat soluble, or hydrophobic.

That property matched the predicted behavior of glucose-6-phosphatase, so they hypothesized this was the gene.

Testing it was straightforward. The enzyme’s function is simply hydrolyzing glucose-6-phosphate into glucose, an assay people had run for decades.

The protein encoded by that gene did exactly that in a test tube.

How the discovery was confirmed in patients

The confirmation came from an unusual piece of luck about who her boss was.

Sid Barry, the scientific director at NIH at the time, happened to work on glycogen storage disease type 1 himself and had patients.

He obtained blood from a patient immediately, and she sequenced that patient’s version of the gene.

The patient had the mutation, which demonstrated that the gene they had cloned was the one missing in glycogen storage disease. It was cloned in 1993.

How gene therapy delivers a working gene to the liver

Gene therapy means putting a good copy of a gene into a patient who has a defective one.

Since the enzyme cannot be purified, replacement therapy was never viable, which left delivering the gene itself.

The delivery mechanism is a viral vector, an engineered virus carrying the gene into tissue where it produces the correct protein.

Adenovirus vectors proved too toxic. Adeno-associated virus vectors, developed by other scientists in the field, worked.

The liver makes an unusually good target. Roughly 90% of a vector infused into the bloodstream ends up there, so liver diseases are among the easiest to treat this way.

My mom’s contribution was engineering a vector that expresses glucose-6-phosphatase at high efficacy.

What the mouse results showed

Newborn mice given a single infusion survived to 70 or 80 weeks.

That result, combined with commercial experience showing adeno-associated virus vectors were non-toxic and could persist in humans for four to five years, is what attracted industry attention.

Companies approached NIH to license her vector and run the clinical trial.

How the clinical trial worked

The company set up a collaboration with NIH on preclinical work required for FDA approval, which came in 2018. The trial began in June 2018.

Administration is simple. A single injection into the bloodstream, with the liver absorbing the vector.

The phase 1/2 trial was designed for 12 patients, and eight or nine had been dosed by the time we recorded.

The results were substantial. Most treated patients no longer needed cornstarch and could sleep through the night.

Two questions remained open: how long the effect lasts, since the data covered only the first year, and immune response to the vector even though it is non-toxic.

Why companies chose this rare disease first

Many rare diseases could theoretically be treated with gene therapy, so the selection is not random.

This one is easy to measure. A single blood test showing glucose levels tells you immediately whether the treatment worked.

It is also a single gene, and gene therapy so far works mostly on single-gene diseases.

The liver target matters too. Diseases affecting the brain are far harder, because vectors have to cross the blood-brain barrier.

That combination of easy delivery and easy measurement is why this disease became an early target rather than a later one.

Janice Chou’s advice for aspiring research scientists

Her first principle is focus. Most people in her lab were told to work on one or two projects deeply rather than attacking ten.

Her own work illustrates it. She developed roughly 80% of the reagents for glucose-6-phosphatase research herself, including the mouse model and the antibody that detects the enzyme, because the commercial antibody does not work.

Becoming the expert is what creates independence. Develop something, become known for it, and people seek you out rather than you applying to them.

Graduate school matters specifically for learning to think independently. Following your professor on everything means never developing your own ideas, and without your own ideas independence is impossible.

Her practical caution is about funding. Research is expensive, grant success rates keep falling, and permanent positions are hard to find, which is why she suggests an MD alongside research so you have medical practice to fall back on.

Why research careers resemble entrepreneurship

My mom worked for the government for 40 years and still ran her own lab, chose her own problems, and pursued her own ideas.

Her framing of why she wanted her own lab is one any founder would recognize. She had ideas about what she wanted to do and did not want to follow other people around.

That is the through-line worth taking from this episode. Entrepreneurship does not require refusing to work for anyone. It means pursuing the work you actually want to do.

The final piece was luck, which she names directly. Follow your interest, follow your talent, and be in the right place at the right time.

Frequently asked questions

What is glycogen storage disease type 1a?

A rare genetic disease affecting roughly one in 100,000 people, where the body cannot convert stored glycogen into glucose. Untreated, it causes hypoglycemia and seizures and can be fatal.

How is glycogen storage disease treated today?

With raw cornstarch every four to six hours, including waking overnight. Cornstarch digests slowly into glucose, which sustains patients between doses.

What is gene therapy?

Delivering a working copy of a gene into a patient who has a defective one, so their body produces the correct protein. For this disease, a viral vector carries the glucose-6-phosphatase gene into the liver.

Why is the liver a good target for gene therapy?

Because roughly 90% of a vector infused into the bloodstream ends up in the liver. Brain diseases are far harder, since vectors must cross the blood-brain barrier.

Why did the glucose-6-phosphatase gene take 50 years to clone?

The protein is highly fat soluble and cannot be dissolved in water, so it could never be purified, sequenced, or characterized using the methods available.

How was the gene finally discovered?

By accident. Janice Chou was isolating genes differentially expressed in a hypoglycemic mouse model, noticed one was unusually fat soluble, and tested whether it behaved like glucose-6-phosphatase.

How many doses of gene therapy are needed?

One. The therapy is administered as a single injection into the bloodstream, though how long the effect lasts is still being measured.

What advice does Janice Chou give young scientists?

Focus on one or two projects rather than ten, develop your own reagents and expertise so people seek you out, and use graduate school to learn independent thinking rather than following a professor.