Australian researchers have made a surprise discovery that could rewrite our understanding of the role programmed cell death plays in embryonic development and congenital birth defects. 

The team showed that, while programmed cell death – or apoptosis – is essential for healthy development overall, many organs and tissues do not require apoptosis to develop normally.

The study, published today in the high-ranking journal Cell, also suggested that abnormalities in cell death processes are likely to contribute to some common birth defects in humans, such as spina bifida, heart vessel defects and cleft palate.

Walter and Eliza Hall Institute researchers Dr Francine Ke, Dr Hannah Vanyai, Dr Angus Cowan, Associate Professor Anne Voss and Professor Andreas Strasser led the research.

X-ray crystal structure of cBOK ∆N18∆C32               Image courtesy of Walter and Eliza Hall Institute

Experiments to determine the crystal structure of a key 'pro-death' protein, BOK, were carried out using the MX beamline at the Australian Synchrotron.

Cell death link to birth defects

Programmed cell death, also known as apoptosis, is a normal process that rids the body of sick, damaged or unwanted cells in a controlled way, limiting side effects and damage to the body.

Apoptosis was first described as having a role in embryonic development in the 1940s. Over the past 70 years, numerous studies have implicated apoptosis as playing a crucial role in most stages and tissues during development.

However, in this new study, it became clear that apoptosis was not as critical during development as previously thought, Dr Ke said.

“Rather, apoptosis was essential at specific places and times during development, but unnecessary in others. We identified the tissues and organs that critically require apoptosis to develop normally, and made the surprise discovery that many do not require it at all,” Dr Ke said.

The finding provides clear clues about a link between abnormalities in programmed cell death and some common congenital birth defects, including spina bifida, heart vessel defects and cleft palate.

“Our research showed that when cell death is not functioning properly, it commonly leads to defects in neural tube development, for example spina bifida, heart vessel defects and facial abnormalities, such as cleft palate,” Dr Ke said.

Surprise discovery

Associate Professor Voss said she thought the biggest surprise came from the discovery of the tissues that did not require apoptosis at all for normal development.

Dr Cowan said the study confirmed that BOK acted as a pro-death protein. “In this paper we have solved the structure of BOK using the Australian Synchrotron, and once and for all confirmed that BOK is a pro-death protein that plays an important role in apoptosis,” he said.

“For some time, it has been a widely-held belief that programmed cell death is necessary for the shaping of certain tissues and structures during development. But, to our surprise, many tissues in which programmed cell death was – for very good reasons ­– considered absolutely essential, it is not required at all," Associate Professor Voss said.

“For example, apoptosis was thought to play a particularly important role in ‘hollowing out’ of ducts in internal organs during development.

"However we have shown that – in the absence of apoptosis – most tissues and organs develop normally. I think it may surprise researchers to learn just how precise and limited the effects of apoptosis are in embryonic development."

The research was supported by the Australian National Health and Medical Research Council, Cancer Council Victoria, Lady Tata Memorial Trust, Leukaemia Foundation of Australia, Leukemia & Lymphoma Society (US) and the Victorian Government.

doi.org/10.1016/j.cell.2018.04.036


Credit: La Trobe University

A team of scientists from La Trobe University has shown a protein found in a tobacco plant has the potential to fight life threatening infectious diseases.

The scientific discovery, published in the prestigious journal Nature Communications could lead to the development of a new class of antibiotics and meet the challenge of rising antibiotic resistance.

Dr Mark Hulett and Dr Marc Kvansakul from the La Trobe Institute for Molecular Science said their team had demonstrated the peptide NaD1 found in the flowers of the ornamental tobacco plant Nicotiana alata has infection-busting qualities.

“Infectious diseases are a major global health problem, accounting for more than one in eight deaths and mortality rates are predicted to skyrocket over the next 30 years,” Dr Hulett said.

“Antibiotic resistance at the current rate will eventually lead to the exhaustion of effective long-term drug options. It’s imperative we develop new antibiotic treatments.”

Using the power of the Australian Synchrotron, the team led by Dr Hulett and Dr Kvansakul have shown in atomic detail how the tobacco plant peptide can target and destroy the micro-organism responsible for a dangerous fungal infection.

The peptide perforates the parachute-like outer layer of Candida albicans cells, ripping them apart and causing them to explode and die. 

“They act in a different way to existing antibiotics and allow us to explore new ways of fighting infections.

“It’s an exciting discovery that could be harnessed to develop a new class of life-saving antimicrobial therapy to treat a range of infectious diseases, including multi-drug-resistant golden staph, and viral infections such as HIV, Zika virus, Dengue and Murray River Encephalitis.”

In 2014, Dr Hulett and Dr Kvansakul found NaD1 could also be effective in killing cancer cells.

Background

Candida albicans is responsible for life-threatening infections in immune-compromised patients, including those diagnosed with cancer and transplant recipients. There are limited effective antibiotics available to treat the infection.

Nicotiana alata flowers naturally produce potent anti-fungal molecules for protection against disease. The plant is related, but different, to tobacco plants grown for commercial use.

DOI: 10.1038/s41467-018-04434-y

 

Today the Australian Synchrotron joins the world in celebrating the International Day of Light 2018

This global initiative provides an annual focal point for the continued appreciation of light and the role it plays in science, culture and art, education, and sustainable development, and in fields as diverse as medicine, communications, and energy. The broad theme of light allows many different sectors of society worldwide to participate in activities that demonstrates how science, technology, art and culture can help achieve the goals of UNESCO – education, equality, and peace.