Excerpt from The Beginner’s Guide to Winning the Nobel Prize, by Nobel Laureate Peter Doherty (Columbia University Press, 2008). Reprinted with permission from the author.
From Chapter 8: Discovering the Future
Dealing with complexity may be the major challenge for science in the twenty-ﬁrst century. Understanding and manipulating the complexities of infection and immunity, or of cancer immunity, provides a continuing, major research focus for those interested in vaccines and therapy. Genomics and the array techniques of ‘discovery science’ have opened the way to scan the totality of the complex genetic ‘read-out’ in a cancer cell or an activated T lymphocyte. Through the latter part of the twentieth century we had great success in the type of reductionist science that looks at the different parts of various molecular pathways. This will continue, with the discovery of novel genes and molecular interactions forming the base of many new scientiﬁc careers. The big questions may be concerned, however, with putting the whole molecular machine together to explain function at the level of the cell, the organ and the organism. As yet, though the triumphs of medical science have been extraordinary, we haven’t even answered such simple questions as what makes a liver grow to the shape and size of a liver?
The great complex and mysterious system that deﬁnes all of us is, of course, the human brain. Here we can expect enormous advances in understanding over the next hundred years. New insights will undoubtedly come from molecular biology and genomics, where individual genes and/or predictable proﬁles of multi-gene read-out will be associated with both physiological abnormalities and psychosomatic disorders, or mental illness. Deciding what to do with such information may not always be straight-forward. Applying new targeted therapies that alleviate debilitating conditions like schizophrenia or epilepsy might seem to raise no obvious problems, but how does society handle a situation where an individual’s DNA pattern is associated with, for example, a tendency to extreme violence and criminality?
The question has already been raised by the genetic correlation between monoamine oxidase A promotor (MAO-A) polymorphism (genetic variability) and a tendency to violent, antisocial behaviour for people with a particular MAO-A genotype. We can’t lock people up on the basis of a tendency. If possible candidates (or their parents) who have committed no crime refuse to be tested, how is this to be handled both legally and ethically? Perhaps some types of severe crimes could be totally prevented by identifying potential offenders as children then providing appropriate counselling or drug therapy; but does society have a right to insist on such intervention in those who constitute a clear risk? On the other hand, if such a genetic predisposition is ﬁrst identiﬁed after the event, is it legitimate to use severe punishments against people who could be said to be trapped by their underlying biology?
Even the schizophrenia and the epilepsy examples are not as simple as they may seem. Though individuals and their families would clearly beneﬁt, effective treatment may also eliminate certain elements of the cultural dynamics that have shaped human society. Most would agree that we can do without either of these debilitating conditions, just as we have no reason to miss diseases like smallpox. However, though treatment with the appropriate psychoactive drugs might indeed have saved Vincent Van Gogh’s ear, would this have been at the expense of his artistic vision and creativity? There is little doubt, I think, that most schizophrenia sufferers would gladly accept any such loss if the medication allowed them to function normally in society.
Fantastic article by Nobel laureate Peter Doherty and colleagues. @Inflammatix_Inc is already decoding the human immune system to diagnose acute infections and sepsis through our HostDx platform.https://t.co/TaHUZrVwWa
— Inflammatix (@Inflammatix_Inc) January 29, 2018
Temporal lobe epilepsy is frequently associated with episodes of profound spiritual experience. Neurologists have argued that the account of St Paul’s revelation on the road to Damascus is, in fact, a classical description of such an epileptic seizure. How different would the history of Western civilisation be if we could time-travel back to the beginnings of the Christian era and give St Paul the twenty-ﬁrst-century epilepsy therapy that may be just around the corner? What do we lose if a more sophisticated understanding of brain function leads to the implantation of electronic chips, or to an extensive pharmacopeia, that modulates the more distressing and debilitating extremes of the human experience? Again, I believe the majority of those who are subject to epileptic episodes would opt to give up the possibility of a spiritual revelation for well-being and the right to hold a driving licence.
Many, if not all, forms of drug addiction are likely to have a basis in how a particular individual’s nerve cells respond to the various neurotransmitters. These are the chemical signals that pass from one nerve cell to another to stimulate the electrical activity that allows the brain to function. A key neurotransmitter is dopamine. Parkinson’s disease, which is classically characterised by tremor, a stooping gait and slowness to initiate and maintain movement, is due to the loss of many of the dopamine-producing nerve cells in one particular region of the brain, called the substantia nigra. These patients are treated with a drug that substitutes for dopamine, L-dopa. On the other hand, people suffering from schizophrenia may have too much dopamine and beneﬁt from being given dopamine antagonists that block neurotransmission and thus overstimulation. Cocaine can inhibit dopamine removal, leaving more around to give continued stimulation. The monoamine oxidase inhibitor that we met earlier, when talking about the genetics of violent behaviour, normally functions to break down dopamine.
It would not be surprising if the application of modern genomic screening, the gene chips that we discussed in relation to cancer, reveals genetic proﬁles associated with neurotransmitter levels, sensitivity, and so forth that determine the susceptibility of any given individual to drug or alcohol addiction. Many of these conditions are likely to reﬂect the interaction of multiple genetic effects or, as they’re known in the genetics trade, complex traits. Knowing that someone is born with a genetic predisposition should lead to more focused education and prevention programs, while understanding the nature of the molecular targets is likely to result in the development of better therapeutic agents.
The nature of drug delivery systems should also improve. Nowadays, if we take a tranquiliser or a sleeping pill, the active chemical is distributed through the blood and binds to the appropriate receptors wherever they may be. Perhaps the application of nanotechnology approaches will lead to the development of drugs that are molecular machines destined to go only to where they are needed. It’s the difference between using police to ﬁnd an offender in a big crowd at a football game, or sending a couple of detectives to a house the guy was seen entering half an hour earlier. The process is both more economical and less likely to result in unhappy side effects.
The other big challenge when it comes to brain function is posed by degenerative eurological conditions like the pre-senile dementias, Alzheimers disease and so forth that are an increasingly serious plague in the elderly. The dementia epidemic reﬂects that human beings—in the developed countries, at least—are living longer than they did even thirty years ago. A lot of this is a direct result of improved preventive treatments for cardiovascular disease. What happens in a condition like Alzheimers is that wrongly folded proteins accumulate in, or around, the irreplaceable nerve cells and eventually poison them: think of the tarry gunk from an oil spill at sea that is washed ashore and chokes the plant and animal life.
Climate change is a health problem. Study Warns of Cascading Health Risks From the Changing Climate https://t.co/doHCFDvV3K
— Prof. Peter Doherty (@ProfPCDoherty) December 2, 2018
One approach is to immunise with one of the offending gunk proteins, called amyloid, so that it can then be removed by the resultant immune response (discussed in chapter 4). However, this has so far proven to be too dangerous. It worked well in mice that were genetically modiﬁed to express human amyloid protein in the brain but, for obvious reasons, the initial human trial focused on people with advanced disease. At that stage, there is so much amyloid around that the immune cells that invade from the blood cause severe symptoms as they try to get rid of it. The best solution is likely to be the development of a small molecule (a drug) that will block the folding process. Even if this only served to delay the onset of symptoms, the beneﬁts not only in terms of alleviating human suffering but also in health economics would be enormous.
One certain development through the twenty-ﬁrst century is that the different scientiﬁc disciplines will work more closely together. This is hardly a new trend, but what is new is that major institutions are taking active steps to facilitate interactions between those who come from different science cultures. The history of Nobel Prizes shows how signiﬁcant this interaction can be: the ﬁrst Nobel Prize in Physics was awarded to Wilhelm Roentgen for discovering X-rays, and the invention of X-ray crystallography by William and Lawrence Bragg led to structural biology, which has been recognised by a number of Nobel Prizes and continues to contribute massively to biology and medicine. The 2003 Medicine Prize went to the chemist Paul Lauterbur and the physicist Peter Mansﬁeld for the development of magnetic resonance imaging (MRI). Nobel Prizes for Chemistry are frequently given for discoveries and technological developments that have their major application in biology, the two awards to Fred Sanger for protein and DNA sequencing being a case in point.
Breakthroughs often result from bringing fresh minds trained in different ﬁelds together for some common purpose. Rolf Zinkernagel had taken a course that emphasised current thinking in immunology, but I had worked previously in virology and pathology and we were both ingénus at the time we did the key experiments and thought ‘outside the box’ about immune recognition. Established theoretical physicists like Erwin Schrödinger (Physics, 1933) and Max Delbruck (Medicine, 1969) made substantial contributions when they switched their interests to biology.
Max Delbruck worked at Caltech after he ﬂed the Nazis, but in 1945 he also started a summer course on the genetics of bacteriophages (viruses that infect bacteria) at the Cold Spring Harbor Laboratory (CSHL) on Long Island Sound, New York. The bacteriophages were the initial research tools that led to the current era of biotechnology and molecular medicine. The summer courses at CSHL continue and—still an intellectual powerhouse—it is legitimately regarded as the ancestral home of molecular biology. A picture on a wall at CSHL shows a very young Jim Watson, of Watson and Crick fame, working there in a summer job as a waiter, while he was a course participant. Jim later served as CSHL director for more than twentyﬁve years and was also the ﬁrst director of the US federal human genome project. He continues in a senior role as CSHL President, and was succeeded as director by the JCSMR-trained Australian virologist, Bruce Stillman. Max Delbruck, Al Hershey and Salvador Luria shared the 1969 Nobel Prize for Medicine, for their ‘discoveries concerning the replication mechanisms and the genetic structure of viruses’. Al Hershey worked at CSHL, and Salvador Luria was Jim Watson’s PhD supervisor at the University of Indiana.
There will be similar science stories through the twenty-ﬁrst century, though only a science ﬁction writer could guess at the ﬁelds of interest, who the characters might be and how the stories may unfold. Apart from improving the human condition, science has a job to do in protecting humanity and the world we live in. What could be the ultimate threat? We have to hope that no person or group is crazy enough to start a nuclear war. One theory to explain the extinction of the dinosaurs is that there may have been a massive asteroid hit, creating such a storm of atmospheric debris that the life-giving rays of the sun were blocked out. No doubt the probability is low, but what could, or would, scientists do to prevent a recurrence? Perhaps we couldn’t stop the hit, but might it be possible to work out how to be independent of solar energy until the dust cleared? We must continue to stretch both our imaginations and our understanding to the utmost. If we want our species to survive in the long term, human beings cannot afford to stop reaching for the stars.
First reprinted by Church and State in 2011.
"The beginner’s guide to winning the Nobel Prize: a life in science"
Book by Peter C. Doherty.
Columbia University Press (2006) pic.twitter.com/rSiX3WGbgV
— Francis Villatoro (@emulenews) December 1, 2016
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