THE COURSE OF CURIOSITY
From fruit flies to human organoids, ELIZABETH FINKEL reflects on the circuitous path of medical advances.
There is a human face to every bit of research – in this case, two. ELIZABETH FINKEL tells a story of determination and revelation, from fruit flys to brain organoids.
IDID NOT BECOME a scientist to cure cancer. I was one of those types who are curiosity-driven; give me the blue-sky mystery and I’ll leap into it. So when in June 2019 Megan Donnell told me she was using research I’d participated in 30 years ago to find a cure for her two sick children, it hit me with the force of revelation: blue sky research really does pay off.
It may be an article of faith inked into your grant proposals, but when you spend your days with fruit flies, as I did in the mid-1980s at the University of California San Francisco, it can be a little hard to believe.
Though I had no medical problem in mind, I was trying to answer a rather profound question: how does the mush of an embryo sculpt itself into a body? At my lab and others around the world, we found the answer lay with a set of so-called ‘pattern-forming’ genes. In the same way that a tailor draws a pattern on a sheet of fabric to guide the cutting and sewing of the garment, these genes lay down a pattern on the newly-laid fly egg to instruct the construction of its body. My gene of interest went by the name engrailed. A few hours after a fruit fly egg is fertilised, engrailed lays down a pattern of 15 stripes along the developing embryo, which provide the pattern to start constructing the 15 segments of the fly grub.
What was so thrilling was that these patternforming genes weren’t just involved in the construction of fruit flies; other researchers found the same pattern-forming genes at work instructing the embryos of frogs, mice and humans. While later researchers delved deeper and deeper to unravel the details of just how pattern-forming genes guide the development of embryos, one stream of this research took a turn that was quite beyond my imagination.
From the early 2000s, researchers began using pattern-forming genes to instruct human embryonic cells to make tissues for patients. Today, advanced clinical trials are offering patients made-to-order grafts for skin, pancreas and retina. Even more startling, the pattern-forming genes are being put to work to make small replicas of human brains in a dish, dubbed brain organoids.
It was Megan who made me realise that this science fiction technology had well and truly arrived. We first met at a conference in September 2018, discussing genetic testing for prospective parents. Members of inbred communities, including Ashkenazi Jews (like myself ), have long availed themselves of genetic tests to ensure they are not carriers of afflictions such as Tay-sachs – a fatal neurodegenerative disease from which infants typically die by the age of four. But members of the wider community are not immune; any couple can wake to the living nightmare of discovering they have passed on a fatal genetic disease to their offspring.
That was Megan’s cautionary tale. A tall, attractive, dynamic woman, her children Isla and Jude appeared normal at birth. But by the time Isla was two, there were concerns. Unlike most toddlers she was not putting words into sentences. Jude was born soon after, and he too had drawn the genetic short straw.
The Donnells were unaffected – and unknowing – carriers of the Sanfilippo gene. Its function is to clear away heparan sulfate, a sugar that holds proteins together in the matrix between cells. Absent a functioning copy of the gene, the sugar levels build up and start poisoning the brain.
Megan and her husband Allan each carried one gene that functioned and one that didn’t. There
was only a one-in-four chance their offspring would inherit both bad copies. Tragically, that was the case – twice over. They were told Isla and Jude would live only to their teens and die paralysed, unable to talk or eat.
The advice the Donnells got from doctors was “have no false hope”. Megan didn’t listen. She did her research and discovered gene therapy.
IT’S A WONDERFULLY SIMPLE idea. For all the profound consequences of a disease like Sanfilippo, its cause is simple: a single gene is faulty. If you could ferry the missing gene to the organ that most needs it, typically using a virus that infects the cells of that organ, you might be able to fix the disease. Megan discovered Abeona, an American start-up spun out of Nationwide Children’s Hospital in Ohio, which was planning clinical trials of gene therapy for Sanfilippo children. A savvy IT business manager, Megan founded the Sanfilippo Children’s Foundation and raised a million dollars. She invested that money in Abeona on the proviso it would carry out clinical trials in Australia.
Megan’s story blew me away. Even though I was editor of Cosmos magazine at the time, we had completely missed the arrival of gene therapy. I suspect we thought of it as a failed technology.
Certainly, there had been disasters such as the death of US teenager Jesse Gelsinger in 1999, when his immune system went into meltdown from the sudden infusion of trillions of virus particles bearing the therapeutic gene. In 2003 tragedy struck again when five children developed leukaemia after receiving gene therapy.
Today’s shining example of the success of gene therapy is a
Though I had no medical problem in mind, I was trying to answer a rather profound question: how does the mush of an embryo sculpt itself into a body?
treatment for children born with spinal muscular atrophy (SMA). Until a couple of years ago, there was no hope for babies born with this condition; they became paralysed and died by the age of two. But babies treated with the gene therapy Zolgensma, marketed by Novartis, have reached the age of four – with many of them walking and some dancing. At a cost of more than US$2 million per treatment, it is the most expensive drug in history.
Spectacular results have also been seen for children suffering from a form of retinal blindness that begins months after birth. A gene therapy called Luxturna, marketed by Roche at a cost of US$850,000 per patient, has restored sight to blind children.
With the lame walking and the blind seeing, paediatrician researcher Ian Alexander at Children’s Medical Research Institute in Westmead, Sydney, has dubbed these “biblical results”. And for the first time that I can recall, medical researchers are using a four-letter word: cure.
Governments and health insurers around the world are now confronted with the dilemma of how to pay these exorbitant prices. Gene therapy advocates argue that one-shot cures end up saving money because most genetic diseases incur costs of tens of millions of dollars through ongoing treatment and hospitalisation. But that calculation depends on whether or not single shot cures such as Zolgensma do indeed last a lifetime, which remains to be seen.
Novartis is offering US insurers pay-as-you-go plans, as well as refunds if the treatments stop working.
But while medical miracles are taking place because of gene therapy, that hasn’t been the case for the Donnell children. In part because they are too old; Abeona trials show that children are most likely to benefit from gene therapy if it is administered in infancy. Once brain damage has begun, it’s difficult to reverse.
Furthermore, in order to qualify for gene therapy trials, children have to be free of antibodies to the viruses that act as ferries for the gene – and one of the Donnell children did carry antibodies.
When I caught up with Megan in September 2019, nine-year-old Isla was back to nappies and Megan was sporting a black eye from her frustrated daughter. But she was far, far from beaten. The Sanfilippo Children’s Foundation is moving ahead on multiple fronts. And once again, I was stunned by what she had to tell me. She was funding a research scientist who was making organoids of her children’s brains in order to test drugs that could slow the progress of their disease.
BRAIN ORGANOIDS proved their value during the 2015 Zika virus outbreak in Brazil. Babies were being born with abnormally small heads, a condition known as microcephaly. But there was debate as to whether the virus was responsible. Researchers used human brain organoids to show that the virus infected and delayed the development of certain types of brain cells.
Megan was now commandeering this technology to make brain
The remarkable ability to make a facsimile of a person’s brain to study their disease relies on the braiding together of two streams of epic research.
organoids for her children. And that, I realised, had been made possible by the convergence of two streams of epic research – both of which I had a connection to.
The first stream delivered pluripotent human stem cells – cells bequeathed with the potential to form any type of body tissue. I had written a book on stem cell development – Stem Cells: Controversy at the frontier of science – in 2005. James Thomson from the University of Wisconsin first learned to make embryonic stem cells in 1998; Alan Trounson’s team in Australia wasn’t far behind. These embryonic stem cells were highly controversial because their source was leftover human embryos from IVF clinics. These embryos were destroyed in order to harvest the stem cells.
Then things got a whole lot more controversial. Dolly the sheep was cloned from a single cell of an adult sheep in 1996. In theory the same technique could deliver cloned human babies. Not that anyone wanted to clone babies; what medical researchers had in mind was cloned embryos. Why? Let’s imagine researchers took one of my skin cells and made an embryo clone of me. They could harvest embryonic stem cells from my 14-day-old clone, which would be perfectly matched to my tissue type.
If, for example, I was diabetic and needed a graft of pancreas tissue, my cloned embryonic stem cells could deliver one – no anti-rejection drugs required. By contrast, if stem cells were sourced from a foreign embryo, I would need to take those drugs for the rest of my life, just as I would for any foreign tissue. Controversial as it was, Australia passed legislation to permit this so-called therapeutic cloning (aka somatic cell nuclear transfer) in 2007.
The explosive debate over human therapeutic cloning was diffused by a single discovery. In 2006,
Japanese researcher Shinya Yamanaka found a magic cocktail – made from just four factors – that reprogrammed skin cells directly into stem cells, no embryo required. These stem cells were given the innocuous descriptor: induced pluripotent stem cells (IPS). As Paul Biegler’s article describes (see page 70), IPS cells are now being made into many different types of tissues, including brain organoids.
But to make those tissues from IPS cells required a second stream of research: the pattern-forming genes I worked on. With a sheet of IPS cells, researchers can now deploy a combination of pattern-forming genes to direct cells towards the formation of any body part, including the brain.
Over the past few years, I’ve read about these developments with great interest. But it was all academic to me till Megan Donnell told me that a researcher was making brain organoids from her children’s skin cells.
In a moment of revelation, I suddenly saw the streams of research converging over the decades. Beginning from those of us propelled by sheer wonder, our research on fruit fly genes trickled down, joining with rivulets emanating from the work of embryo researchers, cloning researchers, and then the torrent flowing from the discovery of the Yamanaka’s factors.
And here sitting in front of me sipping her coffee, was Megan, waiting at the spigot for what this braided stream of research could offer her children.
If I could go back to 1985 and reveal to my younger self – bent over the microscope, peering at fly embryos – just what fruits her research could deliver, I’m not sure she’d believe it.