The 2022 Graeme Clark Oration
Engineering Your Heart’s Health

Would you want to know if and when you were going to have a heart attack? Perhaps not – it is too similar to that age-old question of whether you want to know when you will die – but it might be a different story if something could be done to prevent it.

Professor Natalia Trayanova’s team has developed an artificial intelligence (AI) algorithm to predict potentially life-threatening arrhythmias more accurately than doctors.

Each beat of your heart is preceded by an electrical wave that sweeps through. The electrical connection between cells of the heart and their resulting synchronous behaviour fascinate Natalia.

But sometimes there is a problem with the rhythm – whether too slow, too fast or irregular – which is known as arrhythmia. Many people experience an arrythmia at some point in their lives. Although usually harmless, they can be life-threatening, causing a large proportion of death by sudden cardiac death. If there is a problem with the electrical wave’s rhythm, which is the trigger for a heartbeat, the heart can simply stop.

During a heart attack, lack of oxygen causes part of the heart tissue to be damaged, forming scar tissue. Heart attack victims are therefore particularly prone to irregular rhythms. Scarring can cause the electrical wave before a heartbeat to become disrupted, bouncing back or reverberating rather than acting as a single wave.  The heart stops contracting in a synchronous manner and, in Natalia’s words, becomes more like a ‘bag of wiggling worms’.

People at high risk of cardiac arrest due to a ventricular arrhythmia in the lower ventricle chambers of the heart receive a stopwatch-sized implantable cardio defibrillator. The defibrillator sits in the upper chest to monitor the heart’s electrical activity and delivers a sudden shock to reset the heart should they experience an arrhythmia.

The diagnosis for arrhythmia typically is based on detecting a drop in the amount of blood the heart pumps out with each beat. A “wriggly” heartbeat weakens its strength and the volume of blood pumped falls. Below a certain threshold, and you are considered at risk of sudden cardiac death. However, Natalia does not believe that this truly captures those at risk as it does not reflect the cause of the drop – it may be electrical dysfunction, but it may not.

There are patients who may be at low risk of SCDA receiving defibrillator implants they might not need, putting them at unnecessary risk. Conversely, there are high-risk patients that are not getting the treatment they need, who could die in the prime of their lives. Research into SCDA risk monitoring has mainly taken a one-size-fits-all approach that clearly does not capture everyone.

Natalia’s solution is a more personalised approach. By creating a digital twin of a person’s heart, it can be extensively probed and prodded virtually to predict their risk of sudden cardiac death. Doctors could use this new computer-based method to inform a patient’s treatment plan

The virtual-heart arrhythmia risk predictor – or VARP for short – is the only predictive technology that determines risk of sudden cardiac death. Using MRI scans of a patient’s heart, Natalia’s lab can create a 3D digital model that captures the unique shape of its chambers and its individualised post-heart attack scarring pattern – the most important determinant of arrhythmias. They then run a series of simulated electric currents to unmask any potential problems.

VARP formed the basis of Natalia’s latest technology called Survival Study of Cardiac Arrhythmia Risk (SSCAR) that generates a personalised survival assessment for each patient over ten years.

The name, SSCAR, is a nod to the cardiac scarring that contributes to life-threatening arrhythmias. Given that scarring impacts electrical signals in the heart, this scarring is key to predictions. One machine learning neural network analyses the distribution of scars based on MRI scans. The scars can be spread through the heart in different ways, and each says something about a patient’s chance of survival.

A second neural network assesses patient data, factoring in demographics, physical traits, and lifestyle choices, to link a patient’s background to their risk. Together, the two neural networks comprise SSCAR and can determine the probability of sudden cardiac death. This technology empowers doctors to decide next steps for each patient to prevent future heart attacks.

What can be done if you know that sudden cardiac death is coming? Natalia has figured that out too.

Arrhythmia can be treated with ablation: a spot in the heart is burned. Doctors assess a patient’s heart to find a good spot for ablation, however, there may be multiple places where the rhythm appears off. If the root driver of the arrhythmia is not terminated, the arrhythmia will simply return. In many cases, the arrhythmia does indeed come back, the patient returns to hospital, and they do it all over again – all the while, the patient is accumulating more heart damage.

With a personalised digital heart twin based on a patient’s scans and information, Natalia’s team can find the perfect spot for ablation the first time. They simulate the ablation in potential places of the digital replica and play out each scenario virtually to find the best place for ablation prior to burning a patient’s real heart.

None of the members on Natalia’s team are medical professionals – they are all engineers. Yet in the operating theatre, the surgeons look to her and her team before beginning the treatment. The surgeons ask, “do we do it?” and her team gives the go-ahead. Natalia finds it exhilarating and somewhat surreal that her team is giving such an amazing sense of responsibility in a medical procedure, but it means that patients do not need to come back.

“We have demonstrated that VARP is better than any other arrhythmia prediction method that is out there,” she says.

The Graeme Clark Oration celebrates world leaders and advances in medical research and developments in convergence science. Natalia’s work certainly exemplifies the use of convergent science: technology, engineering, physics, and medicine in collaboration as the future of cardiology. She sees computational approaches and AI as major tools in healthcare and precision medicine. The applause and excitement of the audience was a great indication of just powerful we all believe the future of her work to be.

Written by Catriona Nguyen-Robertson, Science Communication Officer, Convergence Science Network

2019 Graeme Clark Oration: Professor Tim Denison

Towards an Electronic Prescription?

“The brain machine interface – it’s the BMI that could change your life” – Chief Scientist, Dr Alan Finkel.

Seemly taken straight out of science fiction, electronic devices can be implanted into patients to regulate their nervous system in treatments for neurological disorders.

Neurological disorders are a major contribution to disability and death worldwide. Despite decreases in mortality rates from stroke and other disorders, the burden of neurological disorders has increased globally over the past 25 years due to expanding and aging populations. The number of patients who require care by clinicians is continuing to grow. We therefore need new solutions to help us tackle these challenges.

Graeme Clark Orator, Professor Timothy Denison knows that “it’s our first instinct to look to pharma” for the answers. He poses an alternative solution: he is integrating electronics to treat disease in the hope that bioengineering and electric devices will be paired with pharmacology to provide optimal solutions in healthcare.

As the network of nerve cells and fibres in the nervous system use electrical impulses to communicate, it’s no surprise that bioelectronics has significant potential to treat a wide range of neurological disorders. Bioelectronics involves implantable devices that monitor brain signals, and stimulate or block nerve function inside the patient’s body as needed. Hundreds of thousands of patients currently rely on bioelectronic systems inside them to alleviate their symptoms of Parkinson’s disease, epilepsy, chronic pain, and incontinence.

The concept of bioelectronics has been around since ancient times – prior to the discovery of electricity. The ancient Greeks used electric rays (torpedo fish), fish that can produce an electric discharge to stun prey or for self-defence, to numb the pain of childbirth and surgical procedures. The “Torpedo’s shock”, which had the power to stun and numb, was described by Aristotle and Plato, and later taken up by Roman physicians to treat headaches.

Today, neurostimulation is a hot topic in the biotechnology and health spaces, as it has the potential to transform treatment for patients. Direct brain stimulation, for example, is used as a treatment for tremors in Parkinson’s Disease, providing a 20% improvement in patients’ ability to perform fine motor skills. Denison’s aim is to improve this figure without triggering any undesirable side effects. He notes that it’s important to be aware of anything that can go wrong so that it’s possible to find a solution before it does go wrong. With the technology behind brain machine interfaces and bionics rapidly developing, bioelectronic systems can only get better from here.

Denison has developed electric circuits that, instead of merely stimulating the brain, incorporate it into the system as a “co-processor” – allowing for the incorporation of a feedback loop. For example, many thermostats in buildings monitor the environmental temperature and only actively heat when the temperature falls below a certain level. Similarly, electrodes are placed in the brain to monitor brain wave frequency oscillations (the sensorimotor rhythm) and only turn on stimulation when required (i.e. when a patient has the intention to perform movements). Otherwise, the stimulation is turned off. This increases the longevity of the device, uses less power, and decreases the risk of side effects due to stimulation.

There are drawbacks of the current bioelectronic systems as they often remain unchanged in contrast to the rapidly changing and reactive activity of a patient’s nervous system. Denison is developing universal, programable systems that allow these systems to be adaptable for a range of diseases and tailored for specific individuals – it will act as a blank slate that can be moulded on a personal basis.

Advancements of new technologies in healthcare, such as this, are made possible through convergent science. “My background in anthropology has served me just as well as my ability to do calculus,” says Denison. His work has been pioneered by neurosurgeons, neuroscientists and electrical engineers working together, as well as the patients in clinical trials – “they’re the true heroes who will propel this field”. Denison advises that with all these new opportunities for patients, we need to be cautious about neuroethics (ethics associated with our increasing capability of monitoring and influencing the brain) and risk management, and that’s where working in large, interdisciplinary teams come into play.

“The only way to build on science is to build new tools”. Denison’s innovative platform can be easily adapted as our knowledge of nervous systems improves and the technology develops. His devices will allow us to move towards electronic prescriptions based on patient data, seizure prediction and memory improvement in epilepsy, and emotional and sensory processing in chronic pain and depression based on individual needs.

“You can run a brain on four segments of chocolate per hour while a machine would require the power of an entire house to achieve the same processing power” – Alan Finkel. The brain is a truly remarkable organ and Denison’s work is making leaps and bounds to decrease the burden of neurological diseases.

Written by Catriona Nguyen-Robertson |Science Communication Officer | Convergence Science Network

2019 Graeme Clark Oration: Dr Paula Hammond

Nanomedicine Comes of Age

Dr Alan Finkel posed a question to the audience: “To which branch of science do you credit cochlear implant?”  While many may answer biomedical engineering, to Dr Finkel, it “showcase[s] the gifts of material science”. Professor Mark Cook, Director of the Graeme Clark Institute referred to it as “the invisible science” – so hears to material science, the unsung science, which the Convergence Science Network has celebrated annually for a decade as part of the Graeme Clark Oration.

Something so incredible can be built from the simplest of scientific principles that we learn in school: that opposites attract. Professor Paula Hammond, David H Koch Professor in Engineering and the Head of Department of Chemical Engineering at the Massachusetts Institute of Technology, uses this concept as the basis of her layer-by-layer (LbL) nanoparticle technology:

Immerse a negatively charged substrate into a solution filled with positively charged molecules (polycation solution), it will attract the positively charged molecules and they will form a monolayer around the negative core, reversing the charge. The process is then repeated, immersing the now-positive substrate into a solution of negatively charged molecules (polyanion solution). There is no limit to the number of layers that can be added as long as the charge alternates between each layer.

Professor Hammond uses LbL assembly to incorporate a range of different drugs into nanoparticles for delivery into the body. By adding charged polymer layers that degrade at different rates, multiple drugs can be delivered in one go but released sequentially. Similar to Willy Wonka’s Gobstoppers, layer-by-layer nanoparticles can be constructed around any core, with specially designed shapes, sizes and layers. Professor Hammond provided multiple examples of how she has applied this technology to create the new frontiers of medicine.

Assisting bone growth and healing for orthopaedic implants

Currently the sole treatment for large bone defects is surgical intervention. Professor Hammond was therefore interested in creating a less invasive approach to aid bone growth. Her group has created nanoparticles that contain two growth factors: bone morphogenic factor (BMP)-2, which induces stem cells to differentiate into bone cells, and platelet-derived growth factor (PDGF), which promotes angiogenesis, the formation of new blood vessels, both of which are required for proper structural organisation and bone mechanics.  PDGF has to be delivered first (in an outer layer of the nanoparticle) as blood vessels need to form before the area becomes too calcified by bone, and the inner core of BMP-2 is released later.

Orthopaedic implants, such as hip replacements, are associated with a risk of infection, especially when replacing worn out, old replacements. Ironically, bacterial infections undo the work of the procedure as they can cause bone reabsorption, the breakdown of bone. Hence with a sequential release of an antibiotic to clear any potential bacterial infection, PDGF to form blood vessels in the area, and lastly BMP-2 to promote bone growth and healing, Professor Hammond created a one-hit delivery system that complements orthopaedic procedures.

Cancer therapy

Professor Hammond has produced nanoparticles the size of 10-100nm (on par with viruses) that deliver cancer therapeutic drugs, again, with multiple layers:

Stealth layer/outer layer for penetration

To sustain their rapid growth, a large number of tumours undergo rapid angiogenesis (blood vessel formation) to obtain sufficient amounts of the nutrients, but these blood vessels can be leaky. The nanoparticles take advantage of leaky blood vessels to enter and accumulate in tumour tissues. A negative “stealth” layer allows the nanoparticles to specifically target tumour cells as most cells of the body have a net negative charge and therefore repel the negative nanoparticles. Tumour cells are also negative, but the tumour microenvironment can be slightly acidic compared to the rest of the body, and by creating a pH-sensitive outer layer, the outer layer senses when it is in the presence of the tumour and loses its charge. The now-neutral molecule can then interact with and be taken up by tumour cells without being repelled. Additionally, for cancers that do not have leaky blood vessels, the nanoparticle outer layer also contains hyaluronic acid molecules, which bind to a receptor overexpressed on many tumour cells (e.g. in ovarian, non-small cell lung, and breast cancers) called CD44. These methods ensure that the nanoparticles specifically target cancerous cells and leave healthy cells untouched.

Nucleic acid to reprogram the tumour cells

A middle layer of nucleic acids, such as silencing RNA or DNA, silences genes that enable tumour survival or activate anti-tumour genes. Cancer chemotherapy slows down tumour growth, but cancer has the ability to become resistant to many different types of drugs. Cancer cells can spit drugs back out, enhance their repair mechanisms, increase their tolerance to damage that would usually result in cell death, or use other methods to evade death.

In some cases, it is due to MRPI, a molecule on the tumour cell surface that acts as a pump to “spit out” any DNA-damaging drugs used in cancer therapy.  Silencing RNA can be introduced to silence the MRPI gene, allowing any chemotherapeutic to get into the tumour cells. Tumour cells also evade death when they lose the “guardian” tumour suppressor gene, p53. Nanoparticles can also deliver microRNA to restore p53 so that it can carry out its anti-tumour functions. This cargo layer therefore disarms the tumour’s defences before the final blow.

Chemotherapeutic drug core

Chemotherapy can lead to the death of most tumour cells by damaging their DNA, but some drug-resistant ones may survive and grow again. The “one-two punch” approach with the combination of LbL nanoparticle, delivering a nucleic acid to first lower the tumour’s defences, provides great potential to treat more stubborn cancers.

Treating infectious disease

Professor Hammond hopes to apply her LbL assembled nanoparticles to treat bacterial infections. With an outer layer that can penetrate biofilms and/or mucosal barriers in the body (e.g. respiratory tract and gut), a middle layer that contains drugs that weaken bacterial defence mechanisms and kills most bacteria, and an inner core of a final high-strength antibiotic that can kill any persistent bacteria, she hopes that many problematic infectious diseases may become treatable. This is especially important in the face of the global antimicrobial resistance crisis.

Professor Hammond has taken a simple physics concept and applied it in multiple ways. She has integrated engineering, physical chemistry, biology, and medicine to encapsulate and release proteins and biologic drugs in a timed manner, creating multi-agent delivery nanolayered release systems. Professor Hammond’s determination to “create something special - magical almost” and see innovative ideas come to life will ensure that her work continues to be adapted and used for many tissue engineering, biomedical devices, and therapeutic purposes.

Written by Catriona Nguyen-Roberson | Science Communication Officer | Convergence Science Network

2017 Graeme Clark Oration: Dr Harold Varmus

Transitions in Cancer Research

‘Science is based on observation, measurement and deduction,’ says Professor Harold Varmus. The 2017 Graeme Clark Oration, delivered by Professor Varmus, Lewis Thomas University Professor at the New York Genome Centre, focused on the science that provides explanations that continue to change our lives.

Professor Varmus’ life and career in science grew out of an interest in helping others. With parents in the medical profession, he was expected to become a doctor. After several twists and turns, ‘[he] found his footing’ when he studied tumour biology at the University of California, San Francisco. To this day, he endeavours to answer one, single question: how does a normal, healthy cell become a malignant tumour cell?

Cancer is a disease that is part of the human condition – ‘it is inherent in who we are,’ according to Professor Varmus. ‘The reality is that cancer will affect nearly half of us in our lifetimes.’

Our DNA – all 6 billion letters of code – are duplicated every time a cell divides, and mistakes occur often. While our cells tend to have repair mechanisms, sometimes mistakes slip through the cracks. In addition to DNA replication being error-prone, DNA is also subject to rearrangement issues (with regards the way DNA is packaged in a cell in chromosomes) and damage by mutational forces, such as ultraviolet radiation and tobacco.

‘A key aspect of cancer is variety,’ which can make it difficult to study. What unifies cancers is their origin: damage to the genome. This damage can take many different forms in many different genes to affect many different functions in our cells. With increasingly advanced technology, we can better examine changes in genes, look for them in diagnosis, and target them in therapeutics.

Professor Varmus outlined three historical phases of cancer research: the largely observational studies prior to the 1950’s, new experimental biology developing in the late 20th century, and the current boom of faster and more powerful methods to understand the molecular underpinnings of cancer. When Professor Varmus started out as a scientist, it was not feasible to isolate and manipulate genes in humans, but now it has become commonplace and our research capacity has come along in leaps and bounds.

Medical studies prior to the genetics revolution relied on autopsies and observations of cancer cells under a microscope. Epidemiologists also associated cancer with a variety of phenomenon such as age, smoking, or occupation (i.e. exposure to asbestos, mustard gas, or radiation). Paradoxically, toxic chemicals associated with contributing to cancer, radiation and chemotherapy, became the basis of traditional cancer treatments together with surgery. There also appeared to be a strong familial link, thus implicating genetics in cancer incidence.

The advances in phase two of cancer research were reliant on other biological studies: the determination of the DNA double helix structure, the discovery of the genetic code, and the central dogma of biology – that DNA is transcribed into RNA, which is translated into protein. Molecular biology became critical to all forms of research, including cancer research. Armed with a limited ability to study viral genomes, which are much smaller and simpler compared to animal genomes, researchers, such as Peyton Rous, identified viruses that were associated with cancers. Rous could isolate viruses in one chicken and give cancer to another chicken by transferring the viral DNA.

It became possible to identify the specific genes in viruses that caused cancer. Animal cells grown in culture could be infected with viruses and they transformed into tumour cells visibly under the microscope. When researchers asked why viruses contained cancer-causing genes, they realised that these genes were similar to genes in animal cells themselves, hence termed oncogenes. The human genome appeared to contain similar genes that, when altered, would transform a healthy cell into a cancer cell.

Cells undergo a constant, healthy cycle of growth and death, controlled by a set of “go” and “stop” signals provided by regulatory genes. Oncogenes tell cells to keep dividing, growing, and conquering, leading to tumour growth. Understanding this, researchers developed drugs to block protein targets of oncogenes to reverse the effects in malignant cells. Some cancers with commonly mutated genes can be treated with enzyme inhibitors (lung (EGFR), breast (HER2), melanoma (BRAF)), but the effectiveness of this treatment is limited by drug resistance. In the same way that the normal genome can give rise to mutations, mutations that arise in cancer endow it with the ability to adapt and become resistant – it’s a matter of outsmarting cancer.

Phase three of cancer research began with the human genome project, which was completed in 2003. The cost of the initial effort to sequence a single human genome was high, but DNA sequencing costs have since declined exponentially and bioinformatics has accelerated to keep up with the analysis of such large quantities of data. Researchers can now identify common mutations by directly sequencing and comparing cancer genomes. It is still not simple to identify single, targetable cancer genes, as many genes contribute to cancer, but we are getting there.

While our questions around cancer have not changed, the methods we have at our hands to tackle them give us a fighting chance. Professor Varmus is in amongst the forefront of evolving cancer research, and who knows what the innovative technologies of the future will be to aid in finding solutions to current medical challenges?

Written by Catriona Nguyen-Robertson |Science Communication Officer | Convergence Science Network