“A single approach to all individuals needs to be replaced by eight billion approaches acknowledging individuality. Differences between individuals are not there to make our lives difficult. Ecosystem diversity, diversity between the cells in our body, and diversity between the individuals in a town, enhance overall functionality and well-being,” said Hans V. Westerhoff in the second STIAS public lecture of 2024.
Westerhoff is professor emeritus of (synthetic) systems biology and molecular cell physiology at the universities of Manchester and Amsterdam and the Vrije Universiteit, Amsterdam. In an era where mathematics was ‘not done’ by biochemists and experiments were ‘not done’ by mathematicians, he describes himself as “one of the few who got their hands both wet and dry”. This led him from a PhD in Amsterdam on bioenergetics, to a study of DNA supercoiling and antimicrobial peptides at the US National Institutes of Health, back to the Netherlands Cancer Institute and on to three universities, as director of two systems biology institutes.
He is considered one of the founding parents of systems biology with over 100 ex-PhD students and postdocs, and over 500 publications ranging from wet-lab microbiology and molecular medicine to mathematics and philosophy. For over 30 years he has been in close contact with Stellenbosch’s triple J group (Hofmeyr, Rohwer, Snoep – with Jannie Hofmeyr introducing him at the start of the lecture). He was also one of the first two STIAS fellows in 2001, developing Ecological Control Analysis with Wayne Getz.
He is at STIAS to continue his work on developing a new theory on the foundations of biology today which he hopes will lead to new type of, ‘live’, simulations-assisted, book.
He described his passion for science (and life!) as being about the “thrill of one day understanding it all”. His lecture focused in on two key questions: How can chaotic molecules constitute a living cell/organism? And, how can we promote health from disorder?
“With thousands of genes operating in consort, the human body is like Stellenbosch: chaos and order at the same time,” he said. “How can we understand these in concert? Can we ultimately predict outcomes of therapies or policies, or will they remain uncertain.”
“In physics the second law of thermodynamics states that we always go from order to chaos. In biology we are trying to understand how life goes from chaotic molecules to order – to ordinary function in an uncertain world.”
He explained that science used to teach certainty – “if an apple was dropped it would hit the floor and a chicken-laid egg would produce a baby chick, not a puppy. But since 1927 science teaches uncertainty – once Heisenberg showed that particles are not particles but waves, and, that if a particle is a wave, we cannot know/define its precise position and velocity.”
Uncertainty is a feature of all areas of our lives – from public policy, to law, to the anatomical and disease level. As examples, Westerhoff noted that the efficacy of most drugs is below 35% not because the drug has no effect but because it doesn’t have an effect on all people; similarly in the legal sphere – if you enforce the law and limit illegal drug imports, prices increase and new routes are activated – so does enforcing the law work?
At the disease level, he highlighted breast cancer. “About 12% of woman develop breast cancer,” he explained. “70% of breast tumours have overly active oestrogen receptors and these women are usually treated with the drug tamoxifen which binds to the receptors and inactivates them. But 40 to 50% of patients’ tumours develop resistance to the therapy. How do we deal with this uncertainty?”
With much much more information
Westerhoff noted that although physics and biology have come to live with uncertainty in different ways, it was actually Einstein who didn’t entirely agree with the uncertainty aspects of Heisenberg’s waves and pointed to the need for more information about the elementary particles. “Einstein didn’t accept that physics just had to learn live with uncertainty. He maintained that we just need more information which was wrong in physics but what about biology?”
In biology we definitely have a lot more information today.
“The human genome was sequenced in 2000, in 2013 the Consensus Metabolic Map drawn up, and from 2020 onwards we are starting to understand the map at the level of individual cells,” he said. “But with between 20 000 and 25 000 genes this has had to deal with a bewildering complexity. Understanding any individual disease is usually about unravelling multiple problems in the network.”
But he believes biology and medicine are beginning to deal with all this uncertainty. “21st century technologies enable diversification based on individualised information; (functional) genomics highlights the molecular differences between individuals; and, mathematical models can predict disease for every individual separately and design the optimal cure on an individual basis. Uncertainty at the population level turns to certainty at the level of the individual,” he explained.
Westerhoff referred to the example of phenylketonuria – a rare, inherited disorder caused by a genetic mutation in the phenylalanine hydroxylase gene which causes the amino acid phenylalanine to build up in the body and, if untreated, leads to a lack of brain development in babies. Understanding the full pathway of the disease including the genetic sequence, metabolic map, route finding and knock-out possibilities, led to a therapy that works for nearly 100% of cases and is now understood in almost complete detail. “Making order out of uncertainty by access to full information.”
“The vision is to make multiple metabolic maps ultimately; one for each person on the planet; predict their disease(-liability) and improve the mathematics and predictions by comparing predictions to outcomes for more and more individuals, up to the eight billion on the planet,” he added.
And what about at the biological level?
“Each organ is composed of billions of cells. For a long time we dealt with these as if they were all the same but they are highly different if we look at the RNA level.” Westerhoff pointed to recent work by his colleagues and others counting messenger ribonucleic acid (mRNA) which has shown that there are huge differences in the number of mRNA within cells with even, at times, zero mRNA in a cell. mRNA, which Westerhoff described as specialised librarian of the human body, is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a supermachine (the ribosome) in the process of synthesising a protein. The proteins are the many machines of our body, each encoded by an mRNA. He explained in detail the process of protein synthesis which allows cells to grow and maintain themselves. “We found that 800 cells that were identical twins in the sense of having the same DNA and environment, all had mRNA populations, yet none had all the mRNAs needed to synthesise all the protein-machines needed for maintenance or growth: no one cell carried the complete information in the active mRNA form. Yet they maintained themselves and even grew: a paradox. We now resolve this paradox by realising that if they had each mRNA all the time they would produce far too much protein: Since protein is stable, bursts of each mRNA are sufficient for synthesising enough of the corresponding protein for maintenance and replication. Because the mRNA for each protein is synthesised co-operatively when a particular function is required and the mRNAs are highly unstable, the mRNAs appear in bursts. Because these bursts happen in the different cells at different times, only some cells have the mRNA of any particular type at any point in time, though over time each cell has all the mRNAs it needs.”
“This diversity means that every cell/organ can do what it is best at, and there is clear, mutual, collaborative benefit, the same for all,” he added.
And Westerhoff believes we humans can learn from this co-operative, robust and stable behaviour across many domains including complex health, economic and political systems. As one example, he pointed to the advantage of a new type of ‘transdisciplinary’ (as opposed to interdisciplinary or mono-disciplinary) teaching. Here the essence is that students of, say, physics and biology should remain profound physicists and biologists, respectively, rather than become interdisciplinary biophysicists. Yet the biologist should be taught enough of physics for her/him: (i) to understand how physics could contribute to the solution of a, perhaps biological, problem at hand; (ii) to ask the physicist the corresponding questions in such a way that the latter understands them; and then (iii) to understand the answers sufficiently for the problem at hand to be solved. And of course vice versa.
And there is more to be learned: “It’s not about a ‘one size fits all’ solution and no one person can (or even should) do it alone. There is no need for ‘strong leaders’. Rather the opposite: It’s about optimising the contribution from each individual. It is not about managing people but enabling people to self-organise, just like living cells in the context of a human body.”
“Biology and medicine are full of uncertainties and errors but many can now be measured, understood and managed by individual personalised medicine. Diversity benefits the organism as a whole. We will not remove uncertainty, because diversity comes with uncertainty, until we appreciate and then dive into the identity of the individual. Society, equally, is full of uncertainties and diversities, but this should be something we thrive upon in the next phase of our journey from ignorance to better understanding,” he concluded.
Michelle Galloway: Part-time media officer at STIAS
Photograph: Ignus Dreyer