Perlara: Curing one disease. Saving thousands of children.
A Sherlock-like mind of a Bay-Area-based molecular biologist finds cures for rare genetic diseases. What started with a girl named Maggie shall now become a drive to eradicate many rare diseases.
“Not a snowball’s chance in hell.” That was the verdict of what doctors told Maggie Carmichael’s parents about potential treatment for her then 3-year-old daughter. She suffered from a rare genetic disease called PMM2-CDG, which is a minor glitch in the DNA that causes a lot of suffering.
There are many genetic diseases. They are called rare when they affect less than 200,000 people in the US. Maggie is one of about 1000 with PMM2-CDG, which is ultra-rare. She couldn’t walk and barely spoke, and there was no treatment.
There would never be. In most cases, receiving a diagnosis ends a long period of insecurity and starts the road to treatment. Not so with 95% of all rare genetic diseases. Even if a researcher can repurpose an existing drug, the research and subsequent drug trial for the novel use for a rare disease costs at least $5m. The low number of patients makes this no business but a charity. Pharmaceutical companies are not known for their charitable streak.
The plight is real and enormous. Half of all patients with rare genetic diseases are children. Why? Because the chance of surviving such a disease by your fifth birthday is just 30%.
Maggie needs a cure
Sometimes, and only sometimes, the various stars in a girl’s universe align and allow a miracle to happen. In prosaic truth, it is a convergence of events. It begins with Maggie’s parents, Holly and Dan.
They don’t accept fate. Instead, they create a foundation and collect money. They want to find funding and a cure.
One day, eventually, they met Ethan Perlstein. Ethan is a lanky molecular biologist who oscillates between finding cures for rare diseases and making standup comedy about the same topic for everyone willing to listen.
After his PhD from Harvard University and postdoc at Princeton, he founded the first US-American Public Benefit Corporation in Biotech, Perlara.
He recalls meeting Holly Carmichael: “After a few minutes, I thought, am I talking to a mom of two kids with the disease, or am I talking to a fellow scientist? Then it dawned on me that I wanted to build a business and focus science on this problem because I would partner with these amazing people.”
How scientific discoveries are made
Ethan meets Maggie and gets to study her condition. “PMM2 is a form of glycosylation disorder, which means that a single gene is not copied correctly and makes her metabolism unable to process sugar. Which leads to all sorts of grave developmental issues.”
“I wasn’t really trained in rare diseases, but I did my thesis work and my postdoctoral work with yeast and human cells as well”, says Ethan. “While yeast is widely used in research, taking an un-studied gene on a yeast model to find drug repurposing candidates rapidly was not. We didn’t invent anything; we just combined existing methods in a novel way.”
While always humble, Ethan explains the methods of a natural science sleuth: “All these metabolic diseases involve ancient proteins, very ancient pathways. All cells, all animal life do certain metabolic processes almost exactly the same. So we felt we were on solid ground scientifically using yeast, worms and flies to model these human metabolic diseases in children.”
From this starting hypothesis, the scientist extracts the PMM2 gene and lets it react with yeast and a molecule—many molecules, in fact. They can be existing medications, vitamins, or even oils. The lab tests hundreds and even thousands of molecules to find the one that reacts in the petri dish. That molecule is where all the hopes of all the Maggies are focused.
“We discovered a molecule that was never approved in the United States, but in Japan for a different purpose and an entirely different patient population. It’s adults who have diabetes, which is a chronic metabolic disease. And that was the first hint that these paediatric metabolic diseases and these common chronic metabolic diseases could be biologically linked.”
Maggie’s Pearl
When scientists have found a credible solution in yeast or other animals, they must test it in humans. Usually, pharmaceutical companies do these tests on a cohort of patients. That takes time and a lot of money. Two things that Maggie didn’t have, so Ethan and the clinical scientist Dr. Ava Morava-Kocic decided to do an n-over-1 study. These single-patient studies are rare today but have famous precedents.
“Barry Marshall won the Nobel prize after proving that a bacterium causes ulcers”, explains Ethan. “He did this by drinking said bacteria and giving himself the ulcer. That was an N of 1 in its true form.”
In ultra-rare diseases, a single-patient study was the only option, and Maggie became a pioneer, the Neil Armstrong of genetics.
What was a relatively small step in the annals of science meant a giant leap for Maggie. “You can see in a video the before and after”, marvels Ethan. “She had great motor improvement; she suddenly could draw a spiral to color and trace. Her laboratory blood work showed improvements in her balance and coordination as well.”
While Ethan remains the objective scientist, Maggie’s mother has a different story to tell:
“It’s almost like we finally got to meet Maggie,” says Holly. “It was all in there this whole time. She is so funny and has such an amazing spirit, and I can’t even describe it to you because it feels unreal to me that we’re in this spot.”
When speed is an innovation
Bringing a drug to market incorporates a long, fractured, and often inefficient process. The discovery part is usually done in academia, the preclinical work by a small biotech startup, and the clinical work by a big pharmaceutical company. At each step, capital is allocated, business models are created, and money is spent. It can take 12 years to find a molecule for patients receiving the treatment.
Maggie and thousands of other children don’t have the luxury of time. They need a different solution. They need a true renegade scientist who leapfrogs processes that work for a semi-new hypertension medication but not with rare genetic diseases that are potentially lethal.
That renegade scientist is Ethan Perlstein: “The results of single-patient studies prove that it’s not science or gaps in knowledge holding us back. It’s someone who can move lightning fast, spend only what they need, and focus on one. Because one is enough, and if it is enough for one, it might be enough for many.”
She’s also drawing much better. Again – before drawings were just scribbles. Now there are recognizable things that are relevant to and reflective of her life. See this image she drew of Dan. 😊 Letter formation is less shaky and clearer with smoother lines. pic.twitter.com/gGgzuy41zv
— Holly Carmichael (@CarmichaelHolly) August 27, 2020
Getting the treatment to everybody
Single-patient studies were the way to prove that a specific molecule would work with PMM2. However, to bring the repurposed drug to every other patient, a phase-3 trial with many patients is necessary. A new door opens in a story of skill, persistence, and sometimes luck. Maggie’s physician, Dr. Morava-Kocic, one of the world’s leading experts in ultra-rare diseases, brought her institute at the renowned Mayo Clinic to conduct that phase-3 trial. The study is still ongoing at Mount Sinai.
Meanwhile, the scientists at Perlara don’t just twiddle their thumbs. Ethan ticks the box in an imaginative spreadsheet: “1 disease down. 6999 to .””. Yes, that is correct. Due to so many different rare diseases, one in ten Americans has one. Ethan got PMM2-CDG in check, but he and his crew are back to square one for every other disease.
But are they? There are 199 sister diseases of PMM2 in the same metabolic pathway. Synergies can be found.
Accelerating research
We as a society need to accelerate research. Like Maggie, many other children have AARS1/2, another of those genetic bastard diseases. Then there are others who have HARS1/2. Both diseases are different enough to need individual research but close enough to use synergies of research in one go. It’s like one of those buy-4-pay-3 deals.
Maggie’s parents were able to drum up the money for extensive research, but that is an exception. Parents are already stretched thin, dealing with the daily burden of an ARS disease in one of their children. And neither should they go into debt to find cures.
But the scientists can lift research to a new level. Maybe they will find another star that creates many more miracles. And yes, they can.
The exciting prospects of tRNA for longevity
Curing rare diseases is a good deed in itself, but this is not the end. Several studies have indicated that what can be learned from tRNA—which plays a prominent role in ARS diseases such as NARS and FARS—has great potential in longevity research.
“Any living thing that has to convert DNA into protein”, explains Ethan Perlstein. “That requires tRNA synthetases, which is a translation process. The researcher Matt Kaeberlin has shown that you can achieve lifespan extension effects with these tRNA synthetases.”
Having arrived at this point of an incredible journey, it comes as little surprise that tRNA and, with that, the ARS diseases react with Ethan’s yeast model. “It got us thinking that if there is this real longevity hook, and it’s new biology, a new frontier maybe in longevity research that can be opened up, wouldn’t it be great if we can simultaneously help families in the process?” asks Ethan.
It takes a community to fund the cure
Back to funding science. Now, the stars shall align for the kids with AARS and HARS. Ethan Perlstein’s lab Perlara will team up with the community of impact investors Marabou. Together, they will mobilize hundreds and thousands of people to help fund this cause. The immediate funding goal is $150,000, but the sky’s the limit. With every Dollar, more molecules can be researched simultaneously, increasing the odds of finding cures.
This noble cause would undoubtedly be enough to move the community to fund this endeavour, but there is also a tangible reward: every funder receives a share of the molecule’s patent. While this has no commercial value for curing diseases, it can be precious if the patents are licensed for longevity applications. That is a long shot.
For Maggie, finally having a treatment was a long shot. But miracles happen, and Ethan’s lab team, the parents and the Marabou community are ready to make it happen again. And again. And again.
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