Hello and welcome to Research Pod! Thank you for listening and joining us today.
In this episode, we look at the work of New Zealand-born scientist Dr Alan Herbert, President and Founder of InsideOutBio, who gives an honest account of his journey in the discovery of left-handed DNA in his new book, Flipons: The Discovery of Z-DNA and Soft-Wired Genomes. Reflecting personally on the twists and turns over the past decades, his book discusses balancing risk versus reward when challenging norms and pushing new boundaries in the quest for scientific discovery, in turn changing the way we view DNA and genetics in the evolution from old to new thinking in this field.
‘It’s in the genes!’, they say. Our DNA and genetic makeup make us uniquely who we are, but is that the whole story? Even identical twins are not identical so our genome is not our destiny – but what changes a person’s fate? Since its discovery in 1953, the double helix structure of DNA was believed to exist only in a conformation where it twists to the right, known as B-DNA. All the information needed was statically coded in the sequence of DNA using the famous triplet code based on codons.
However, in 1979 scientists expecting to see the Watson and Crick helix in their crystals instead saw DNA that twists to the left rather than the right. The strands had a zig-zag backbone so they called it Z-DNA. No one knew what to make of it and pretty soon everyone thought it was best to ignore the finding as ‘just one of those things.’ Fast forward forty years and imagine everyone’s surprise when the Z-DNA was found to have important biological functions. Z-DNA represents a different way of encoding information in the genome. By changing shape, DNA can switch responses. The DNA sequences that flip from one conformation to another are called ‘flipons.’ Whereas codons are static and fixed, flipons are dynamic and change shape to alter the way RNAs are made from our DNA. Rather than genomes being hard-wired with our destiny fixed, the readout of information is soft-wired with many alternative outcomes possible. The DNA can flip from one conformation to another and switch how a cell is programmed.
This new knowledge is changing the way we understand health and disease. Central in this elucidation was the work of Dr Alan Herbert and his collaborators. Herbert coined the term ‘flipons’ because of the ability of DNA to flip from one configuration to another. He discovered a protein that binds Z-DNA tightly and has provided a tool to map the pathways in which Z-DNA is involved. Work from many scientists from several disciplines has now provided the critical evidence to confirm the biological role for Z-DNA. The knowledge has fundamentally challenged thinking on how our genetic information is encoded. Instead of by sequence alone, the shape of DNA alters how programs are stored in our genome. In his book, Flipons: The discovery of Z-DNA and soft-wired genomes, Herbert now gives an open and unfiltered account of his journey to this scientific discovery, describing the challenges faced and discussing the importance of risk taking to progress science.
The chance discovery of Z-DNA in 1979 created a major hype with speculation growing as to the role of this left-handed DNA in biology. However, over time sceptics began to conclude that Z-DNA did not have a biological function and wrote off any significance, sometimes quite harshly. ‘Who cares if you can twist right-handed Watson-Crick DNA the opposite way?’
The relevance of Z-DNA was repeatedly challenged with this area of research often viewed as a low priority. In a long journey, ‘swimming upstream,’ Herbert persevered and in a series of papers from 1993 to 1997, he and his collaborators discovered a protein that bound tightly to Z-DNA. Herbert called the left-handed binding domain Zα. However, it was not until years later that he was able to provide genetic evidence in humans for a biological function, a finding rapidly validated by many other labs. Intriguingly, the Zα domain was found in an enzyme that can edit the sequence of RNA after it is copied form the genome, suggesting that flipons may dynamically switch the readout of genetic information. Indeed, it is the recognition of a left-handed form of RNA called Z-RNA that helps cells respond to threats from viruses and cancer cells. A key distinction of flipons that form Z-DNA and Z-RNA is that they alter a cell’s programming by changing shape without altering the DNA or RNA sequence. In contrast, codons must alter their sequence to change a protein’s function – then the previous function is lost. Flipons allow many different versions to be made with the context deciding the one that is best for the job. Herbert’s current work focuses on therapeutics that can change flipon conformation to help fight cancers and on others that can reprogramme cells therapeutically.
Herbert highlights the age-old struggle in science between the old and the new. Science, whether good or bad, can be propagated through the literature and become the accepted norm. Any findings that do not fit the established norms are termed ‘not relevant’ and often dismissed. The unorthodox ideas go unfunded. Herbert remarks in his book, ‘The financiers are guided by their perceptions of what is possible.’ He goes on to discuss the time it takes for new ideas to be accepted. For example, it took considerable time for the scientific community to accept that different conformations of Z-DNA enable variations in the encoding of genetic information. Long before that, the concept that DNA itself is indeed the genetic material in our cells was initially refuted. Quoting Francis Darwin, Herbert notes in his book, ‘It is always the case with the best work, that it is misrepresented, and disparaged at first, for it takes a curiously long time for new ideas to become current.’
‘Nothing ventured nothing gained’ and the scientific hierarchy
Herbert’s book discusses the dilemma scientists face when wanting to explore something different and higher risk with his belief that funders favour low-risk projects. Proposing higher-risk research may minimise funding chances with potential devastating career effects. However, ‘stepping out of line’ as he says and taking risk can lead to significant discoveries with great reward. Researchers may therefore be pulled in both directions and feel conflicted when choosing to pursue unpopular projects. With those just starting out on their careers in mind, Herbert provides a survival guide to coping with all the challenges that arise when you take the road less travelled. There will be many surprises along the way, both good and bad, and no guarantee that the journey will be successful. Provided the odds are favourable, rolling the dice is the only way to be ‘lucky’ enough to win.
ResearchPod was also privileged to ask Dr Herbert some questions, starting with why his research focus inevitably kept returning to Z-DNA…
“I thought that the question of whether Z-DNA had a biological role was interesting and important. I also believed that people were mistaking an absence of proof for a proof of absence. At any one time, you can only do what you can do. It is important to choose the battles to fight where the odds are in your favour. That means having the methods to address the questions that are of the most interest to answer. I describe that history in the book. I was also lucky in a number of ways with the timing and that during the times I was working on something else, the Z-DNA and Z-RNAs field was not something biologists were actively exploring. Now with the explosion of data and the analytical methods we have, it is possible to test many different hypotheses computationally and eliminate wrong explanations. That helps focus future experiments. By focusing on flipons, I have been able to explore many different fields and provide a framework for reinterpreting many of the earlier findings. Fortunately, in the age of the web, the papers generated are well indexed by search engines and can be found by searching with the key words ‘flipons, DNA, RNA.’ I have no doubt that better explanations will be found, but for that to happen, someone needs to perform the experiments that they have not thought to do in the past.”
When asked why he wrote the book and why now, Dr Herbert remarks that:
“The field has come together only recently and it surprises me constantly how little people read outside their own work. They track their colleagues and then rely on word of mouth to learn the rest. There are now three decades of scientists whose only knowledge of alternative DNA conformations may have come from a single mention in their undergraduate courses, followed by ‘Don’t worry about this as it has no biological function.’ There was the need to reach a larger audience to help foster interest in funding more work by others on flipons. Also, I thought it would be helpful for more junior scientists to have their contributions to the Z-DNA and Z-RNA field recognised by a wider audience. As the saying goes, ‘A rising tide raises all boats.’”
When asked what the future of Z-DNA/flipons research may look like, Dr Herbert considers that:
“The only thing that I am sure of is that there are still many more surprises to come. What is limiting now in the basic science is the methodology to track flipon conformation in real time in real cells and follow the effects of the switch from left- to right-handed DNA on outcomes. What is an interesting engineering challenge is to develop ways of manipulating flipon conformation to change the genetic programming of cells to offset the effects of disease and ageing. Flipon-based biosensors also may overcome the limitation of trying to pack silicon-inspired biocircuits into cells – that technology does not scale well to the size of cells. There are only so many of these types of logic switches that you can build into the confines of a cell. Contrast that with how a cell works using thousands of flipon switches to program itself. Also, as a bit of a tease, there is now a developing story of how flipons contributed to the origins of the genetic code.”
That’s all for this episode, thanks for listening. Links to the original research can be found in the shownotes for this episode. And be sure to stay subscribed to ResearchPod for more fo the latest science!
See you again soon.
