Gail Risbridger Junior Scientist Award Winner Akhil Gajipara
Many PhD students feel like they’re toiling in obscurity on the world’s tiniest problems. For Akhil Gajipara, this was literally true – until he presented his work to the ESA’s Annual Scientific Meeting and immediately won the ESA Gail Risbridger Junior Scientist Award.
Akhil’s presentation on nanoparticles promised a completely new and safe way to treat genetic hormonal conditions. This came as astounding news to everyone but Akhil – he’d been working on the problem for years but couldn’t share his discovery until the intellectual property protections had been resolved.
“I had to wait for almost 3 years to present my work. In the meantime it was difficult for me [in terms of funding and career progression], but [then] I presented this work for the first time and got the award,” says Akhil.
“It’s a big thing for me, it’s huge.”
Genetic diseases and many endocrine diseases are often seen as incurable, with patients and their doctors given the lifelong task of managing symptoms. Akhil’s research proposes that some genetic diseases might be curable after all.
“For endocrine research, it’s very unique because very few have used nanotechnology for endocrine disease. I think it [this project] is the first thing, actually.”
“[in conference presentations] it’s completely new for all the people that I’m bringing this new cool research in the endocrine system [to], and they are also very excited to see how things are going and how it’s working in the adrenal gland.”
Good things come in small packages
Nanoparticles are tiny little blobs manufactured to do microscopic jobs in teeny places.
“Back in 2016 it was completely new field,” explains Akhil.
“Before this technology got into healthcare it was there in the semiconductor industry as well as in environmental science where it was used as to remove contaminants from the water and that kind of stuff.”
“During that time, I got interested to work in this field because it has huge potential for healthcare applications, and it has very low costs as well as huge impact on the healthcare field.”
“COVID-19 vaccines are also based on nanoparticles. which were developed by Pfizer and Moderna. They are based on the same kind of lipid nanoparticles that I have worked on for this project. And now many researchers are doing things using these lipid nanoparticles in cancer treatment.”
Akhil’s particular focus is on developing new treatments for people who have genetic diseases, and he’s started with disorders of the adrenal gland.
“Currently in adrenal disorders, there are no permanent cure for these diseases,” says Akhil.
“The only cure is hormone replacement therapy, where people with adrenal disease are given synthetics steroids to replace the hormones and correct the hormonal imbalance in the body. They have to take it every month or every week [for the rest of their lives] and there are side effects of using synthetic steroids as well.”
“So this nanotechnology will be a lifelong solution, because it will permanently integrate the … functional gene [into the patient’s adrenal cells] and cure the disorder permanently.”
Every cell in the body has a genetic code that tells it what to do and how to do it. Genetic diseases happen when there’s something wrong with that code, and the cell can’t do its job properly.
Akhil’s nanoparticles deliver working genes into the adrenal cells to replace the defective genes that cause disease.
They’re designed like a microscopic jam donut: a fatty lipid blob dusted in sticky peptides and carefully filled with hot genetic jam. Once these tiny spheres enter a body, they head straight to the adrenal gland, glom onto to adrenal cells, insert the new genes inside the cells, and then dissolve into harmless goo. The cells then start using the new functional gene instead of their existing dysfunctional genes, and the adrenal gland starts working properly.
“[the nanoparticle itself] is just used as a carrier to deliver the gene of interest to the body. Once it delivers the gene of interest, it just decomposes in the body, and it will be excreted from the body via the hepatobiliary and urinary routes.”
While Akhil specifically looked at the adrenal gland for his PhD project, he’s confident it could be used for all sorts of genetic endocrine conditions in the future. The method can be used for any organs – the only difference is in telling the nanoparticle where to go.
“The nanoparticle will remain the same, but [for this project] we put adrenal targeting peptides on the surface of the nanoparticles so this peptide can specifically attach to the adrenal gland and it won’t go anywhere else in the body.”
“That’s why this nanotechnology is so powerful – it only targets organs of interest and doesn’t go everywhere, so it will be less toxic to the body whenever you put it as a treatment. So it will decrease the dose of the treatment as well. [And] you can specifically target genes in specific organs.”
“Another major benefit is that these nanotechnologies are compatible [with the body’s own physiology], which means that it doesn’t have any toxicity to the body at these doses,” Akhil says.
“We have tested multiple doses, and we haven’t seen any side effects of using lipid nanoparticles, because these lipids are a component of the body, and thereby compatible, and didn’t affect any organs in the body [other than the ones they wanted to affect]. So it’s very safe to use as well.”
While this treatment deals with genes and genetics, it only works on one specific organ and doesn’t affect the reproductive glands, so it isn’t passed on to future children.
Mice work if you can get it
Medical research is tested on mice before it’s done on humans. Mice are very similar to humans in that they have eyes and legs and are scared of doctors, but human endocrine systems just aren’t as squeaky or as cute as mice endocrine systems and this makes it difficult to use mice for human hormone research.
To solve this, researchers put a lot of effort into making special genetically modified mice that do have some of the same endocrine features as humans – these are called mice models. But it can take a lot of time and money to breed these special mice, and that’s before any research has even started.
Akhil’s team managed two huge feats that might make things better for researchers and for the mice.
They not only managed to insert a human gene into the mice’s adrenal gland and keep it there (a difficult task, given that mice have particularly feisty adrenal glands), but it started working inside the mouse to produce human hormones. Other researchers had attempted this, but had only been able to get it working for a short time.
“There is a huge physiological difference between the human and mouse adrenal gland … That’s why we tried to put the human genes into the mouse adrenal gland, so we can minimise the gap between the human and mouse adrenal physiology to study the human adrenal disease in the mouse model” says Akhil.
For genetic diseases, researchers also breed special mice called knockout mice, where certain genes are knocked out of action. This also takes time and money and a lot of sick mice are created in the process. Akhil’s team used their nanoparticle technology to directly knock out genes in the adult mice, so special ones didn’t have to be bred.
“We also tried to develop a disease mouse model using shRNA, with nanoparticles. ShRNA can bind to the gene of interest and decrease the expression of that particular gene. So the gene won’t work at its full potential and can’t get the hormone synthesised at its full potential, and this will create disease condition in the mouse,” explains Akhil.
“So, we tried to achieve that as well, using this same lipid nanoparticles, and we were successful in this as well. We were successful to create the disease state mouse model in just two weeks, which is a major animal welfare benefit.”
“And it cost us around, I think, $4,000, as compared to $35,000 to $40,000 in conventional knockout pass.”
Celebrating the small wins
Now he’s finally allowed to talk about his work, Akhil wants us to know that it was hard.
“When I joined my PhD, in the first phase, it was not working at all. Like, we were very upset. We needed to optimise the concentration, and components, and the ratio between gene and nanoparticles … our team tried lots of formulations. It took a huge effort to get optimised nanoparticles, so yeah, I’m very proud that we have optimised that.
“And the adrenal gland – to get gene alteration in the adrenal gland, is very hard, I would say, because it’s very dynamic organ. And whenever you put something in the adrenal gland it will affect the other [elements of the] endocrine system as well, like the pituitary gland and the gonads. So we have to maintain those organs as well, and we have to study every aspect of the endocrine system.”
But the most difficult part for Akhil wasn’t convincing his supervisor that he was working hard on invisible things and not just pretending. The hardest and most important thing was coming up with a foolproof procedure – a system to create identical, standardised nanoparticles that would succeed every time.
“The production and the development of these nanoparticles takes a lot of effort because we need to be very consistent,” says Akhil.
“We need to get a nanoparticle of consistent size with the consistency of delivering the gene efficiently every time we put this in the mouse model, because we need to repeat my experiment multiple times, and need to get the same nanoparticles, with the same concentration, with the consistent size, every time.”
“So I developed a procedure and established a protocol where I can just use the same formula, same methodology, and can get the precise nanoparticles [every time].”
“So that was a major part of my PhD project, and I am very proud that I achieved this synthesis and development of this technology.”
Bryan Hudson Clinical Endocrinology Award Winner Josh Gialouris
“I just want more men and clinicians in general to be thinking about male reproductive health,” says Josh Gialouris, winner of the ESA’s Bryan Hudson Clinical Award.
Understandable, since he did his award-winning research on the only medically treatable cause of male infertility: Hypogonadotropic Hypogonadism.
Hypogonadotropic hypogonadism, or HH for short, is a rare but treatable condition where the brain doesn’t communicate properly with the testicles. This means the testes can’t make the right amount of testosterone or sperm.
“One problem we have in this area is it’s hard to explain without using the jargon. And it’s something that I encounter with patients all the time, trying to explain to them what’s going on,” laments Josh.
“[in HH], the testes have the ability to make testosterone, and to make sperm, but they don’t receive the appropriate simulation from the brain.”
“The brain contains the pituitary gland, which is a little pea-shaped gland just behind the nose. And that little pea-shaped gland produces hormones, which tells the testes to make sperm and testosterone.”
“People with Hypogonadotropic Hypogonadism are lacking the hormones from the pituitary that tell the testes what to do,” Josh explains.
“And for that reason, they’re usually deficient in testosterone, and are lacking sperm. Usually, the testes themselves, if they’re exposed to the right stimulation, the right hormones, which we call gonadotrophins, they can respond. They can make testosterone, and they can make sperm.”
“That’s different to … Klinefelter [syndrome] or other diseases – which are actually more common causes of male infertility – where there’s a problem with the testes themselves,” says Josh.
Happily, there are relatively easy treatments for HH. Men who aren’t planning babies can get their testosterone as a gel or quarterly injections PBS-subsidised. Men who would like to have a baby need to be injected with partially PBS-subsidised gonadotrophins a few times a week to activate the testes.
“We can replace the hormones that the brain would normally make in order to stimulate the testes to make sperm and testosterone,” Josh elaborates.
What doctors didn’t know in great detail was how this condition and its treatment would affect a couple’s ability to fall pregnant. They knew that the gonadotrophins would stimulate the testes to produce sperm, but not the fine details of how long it took or how the quality and quantity of the sperm might be affected during the course of treatment.
Complicating things further is the fact that HH has lots of different causes. While some men might be aware of their condition from a young age, others only find out when they try for a baby. HH can have a genetic cause, or result from a benign tumour or injury to the brain. Often, men have been told contradictory or outdated information about HH and fertility.
Josh’s research, looking at all the records of all the men with HH who had been through Concord Hospital’s Andrology Department, showed that gonadotropic treatment worked so well in improving fertility that the biggest limiting factor for couples affected by HH was the woman’s fertility status.
This isn’t to say that HH doesn’t have any consequences. For some men it can take years to get diagnosed with HH and get treatment for it, and years matter when it comes to fertility – especially the ones over 35.
Gonadotrophins also take time to work, which means many couples face a choice: take the medication, wait months for sperm levels to slowly rise to a normal level, and then try for an unassisted pregnancy? Or take the medication and surgically extract a small amount of sperm as early as possible to use in an assisted reproductive process?
“You have to think: do you wait for a natural pregnancy, which can take longer as it takes time for the man’s sperm count to increase sufficiently – or do you go early for assisted reproductive technology (IVF and ICSI), which is more invasive, but where you can get small amounts of sperm to fertilise an egg and cause a pregnancy earlier?” questions Josh.
A supportive workplace makes all the difference
Giving patients the right information to help them navigate these delicate dilemmas is what draws Josh to research.
“Often the research questions come from niggling questions you have in clinical medicine, things you wish you knew the answer to, or things you wish you had a better approach to,” he says.
“I think it’ll be a bit of a mix of clinical medicine and research throughout my career because, for me anyway, it works well to do both.
“Working clinically in reproductive endocrinology is quite rewarding.”
“Often the conditions are treatable and so you get to have some good outcomes with your patients – and, you know, if everything goes well, often the couple ends up with a baby, which is obviously really quite an amazing thing to be a part of.”
While the Bryan Hudson award recognises Josh for his efforts, it also demonstrates the importance of dedicated research centres structured around long-term goals, a supportive culture, and cross-discipline collaboration.
“The Andrology department [at Concord Hospital] is really excellent,” Josh commends.
“It’s the only dedicated andrology department in the country. The department has been treating patients and conducting world-leading research for decades.”
“There’s also a lab there on site that performs the semen analyses, so other than doctors and nurses the team includes laboratory scientists as well. And there’s another lab close by which was useful for my blood profiling, so there’s a lot of unique aspects with the department. The department has a lot of really experienced clinicians and researchers, so working there was a really fulfilling experience.”
“It was a unique opportunity where we had quite a large cohort of men with this particular condition. It is probably the most comprehensively studied cohort in the world, and one of the biggest cohorts available in the world, because [the department has] been there for so long (over 40 years).”
“Working there also provided a great lifestyle because that kind of work is a lot more predictable and plan-able compared to clinical work. Medicine can often have unpredictable and long hours so it was a great opportunity to have a bit of a normal life for a year as well.”
Teamwork makes the dream work
Josh is planning to continue with reproductive endocrinology, but after spending half his life in medical training, he’s off travelling around Australia with his wife, a qualified veterinarian who’s taking a year to practice country animal medicine.
Before he heads out, there’s just one thing he wants us to know first.
“Here we have something that’s rare, but it’s really treatable. And we don’t want men who could be treated to go undiagnosed or not to seek medical help when they’re experiencing problems with their fertility, or if they’re just not feeling quite right in themselves and think something may be wrong with their reproductive health.”
“There’s a lot out there that can affect men and their reproductive health and I just really want them to seek help when they need it and consider it in their lives – and for clinicians to support them when they do seek help.”
