Article 8: Garret FitzGerald

Molecular Clocks, Translational Success, and Human Phenomic Science: Garret Fitzgerald’s Panoramic View of the Future of Human Biology
 

Every human is a multiplex of ecosystems. The balance of symbiosis and competition from within is as critical as maintenance and defense systems like inflammation to achieve homeostasis. These adaptive processes occur at different stages in different scenarios, all over the body at the same time and often unnoticed. How are the streams of molecular and cellular players coordinated in systemic responses that maintain integrity of the whole?

Pallavi Devchand, Eric Schadt, Garret FitzGerald, Frontiers in Pharmacology, 2023

Narratives of Discovery

 All non-referenced quotes are the words of Dr. FitzGerald

A long, uninterrupted conversation with Garret FitzGerald exposed a multiplex of his own ecosystems. His searching investigations of seemingly unconnected biological questions—prostaglandins in inflammation, aspirin and risk of myocardial infarction, bioactive lipids in cellular signaling—contribute to a coherent universe of scientific thought. Known for his break-through molecular biology work in the thrombotic hazards of Cox II inhibitors and more recently the relationships between molecular clocks and resilience and aging, FitzGerald has accrued a coherent or at least visionary view of the nature of scientific investigation.

FitzGerald’s lab at the University of Pennsylvania’s Institute for Translational Medicine and Therapeutics is a discovery incubator for gifted  investigators. Ask his post-docs: not only are they encouraged to develop their own research questions. They come to expect that their PI will get as filled with wonder as they are in gazing at their own powers of thought. He advises them to develop “focus and persistence. Humility, too, is needed when you turn out to be right but have the humility to keep listening to others as you continue down the road of science.” Finally, after a pause, he adds, “These stories usually take a long time to tell.” 

The problems that FitzGerald has pierced over the years can only appear coterminous from a bioscientific Karman’s Line denoting the edge of space, as if he’s escaped earthly boundaries. He steps easily from the study of eicosanoids to the role of temporality in health care quite beyond the certainty of death. We have come to anticipate FitzGerald’s high-altitude observations that come, not from on high, but from a confident if necessarily speculative position of both erudition and optimism.

Rather than providing an overview of the work of a career, I have chosen a few milestones in FitzGerald’s recent work as evidence that an eminent molecular biologist has come to use his stature to all the better see into the future—and to use that futurist vision to improve the health of the public. A 2005 single-author Perspectives essay in Nature Review/Drug Discovery, “Anticipating Change in Drug Development: The Emerging Era of Translational Medicine and Therapeutics,” called for translational science simultaneously with the unveiling of  Elias Zerhouni’s Roadmap.[1] His 2015 “Molecular Clocks and the Human Condition” published in Diabetes, Obesity, and Metabolism unveiled tantalizing evidence of coherent systems of molecular clocks in diverse organs and tissues.[2] A 2018 multi-author multi-continent paper in Science called “The Future of Humans as Model Organisms” proposes the creation of human phenomic science as an emerging form of bioscientific investigation that could eventually cohere vast stores of multi-omic, electronic medical record, and deep phenomic data to accelerate personalized or precision medicine.[3] Finally, a 2023 paper, “The Circadian Biology of Heart Failure,” marshals findings to date in molecular clocks’ functions in congestive heart failure, from its genetics and electrophysiology to clinical chronotherapy.[4] Published between 2005 and 2023 in diverse scientific journals with a variety of co-authors, these papers hint at the nature of thought going on in this investigator’s consciousness.

In the same month that Zerhouni announced the NIH Roadmap for clinical and translational sciences, FitzGerald published in Nature Reviews an urgent call to basic life scientists to prepare the scientific workforce for the future in drug development. His meta-view here takes in the dearth of new drugs coming to market, global competition, industry’s profit margins and proprietary hoarding, and public negative perceptions of pharma. He argues that, unlike industry, academic centers have access to the vast range of scientific and clinical disciplinary expertise—and the stamp of academic authority—needed to propel break-through discoveries. They also have access to patients. This call challenges academic centers to grow life scientists and clinicians in the cross-over capacities now segregated in departments of cellular biology and pharmacology and informatics for agile movement toward patient-oriented research and individualized medicine.

"Founding such a discipline is a substantial and expensive challenge. Rather than being a transient and peripheral endeavor within a single company or academic medical centers [AMCs], it challenges the current structure of drug development across the pharmaceutical industry and the organizational units with AMCs. . . .  It is rich with opportunities to provide benefit to public health and to interact with both industry and the FDA in novel and productive ways." ^{1, page 818}

See how his vision rises above loyalty to either partner in this collaboration, desists from ideological debate or blame, and appeals to the best in each domain while not pulling punches on costly narrowness and greed.

In the 2015 co-authored paper published in Diabetes Obesity Metabolism, FitzGerald marshals growing evidence that points to the existence of molecular clocks not only in the master pacemaker in the brain’s suprachiasmatic nucleus but in a plethora of tissues and organs. In our interview, he says:

FG: " I'm very interested in molecular clocks because they are a system that integrates  function across different tissues and coordinates them. I'm interested in the possibility that the disintegration of that consolidation may be an early signal of the  trajectory of the aging process"

Genes controlling clock functions have been isolated and used in knock-out and knock-In studies. Garret and his collaborators find that “up to half the transcriptome [in rodents] is subject to circadian oscillation. . . . We have some evidence consistent with a role for clock dysfunction in human disability and disease” ^{2, p. 139}. Investigators have documented temporal oscillations in such events as asthmatic exacerbations, attempted suicides, stroke, and myocardial infarctions. Drugs, we are learning, can be most effectively dispensed in accord with the physiological clocks that govern the phenotypic feature in question. Beyond genetic oversight, physiological clocks epigenetically modulate the organism’s response to environmental factors.

RC: "And the connection being made between some of these clocks and the onset of dementia?"

FG: "Certainly at a descriptive level, we know that people who deconsolidate early their sleep-wakefulness cycles are people who tend to develop early Parkinson's disease or other types of neurodegeneration, and obviously that sort of information isn't proof of a causative relationship. It's more a correlative relationship, but we're interested in the possibility that it may actually reflect a causative connection. . . . What’s obviously interesting to do is if we could predict the people who would be likely to pursue an accelerated aging process before it's evident that they have."

The common thread in translational science and molecular clocks is Garret’s recognition of integrative thought within the life sciences. He pushes us to transcend reigning paradigms to entertain emergent concepts that challenge status quo—from how to train bioscientists to perform frontier work in drug development to how to identify the transcriptional locus of control that supersedes genetic determination of phenotypical traits.  

Garret predicts developments in the sciences. The 2018 paper in Science rather grandly calls for another collaborative bioscience: “The future of humans as model organisms: a ‘human phenotypic science’ approach could accelerate personalized medicine.” Not unlike his anticipation of translational research and translational science in 2005, he knows how much we already can do in identifying individuals’ phenotypic traits through the gathering of a multitude of data.

RC: "Are the currents within bioscience permitting or encouraging or getting in the way of this kind of integrative thought?"

FG: "Well, people are much more conscious of it than . . . a decade and a half ago [when] people were much more focused on . . . genetic variants. . . . The genetic variability, which is very important, is really one hand clapping because what you really want to know is how the unmeasurable or unmeasured environmental impacts on our individual genomes result in  functional variants in response. . . . The trick is to integrate the genetic data, those other types of outputs and into functional response."

Calling for the future of humans as model organisms is short-hand for an expectant futuristic regard for bioscience’s powers. Our capacity to cohere the genomic, proteomic, transcriptomic, metabolomic, and other data with environmental forces, behavioral choices, and what wearables capture may subtend “a better grasp of the dynamic relationship between genes and the environment [to] truly sharpen our ability to determine disease risk and response to therapy”^{3, p. 552}. Separating this material into “light phenotyping” and “deep phenotyping” lets Garret acknowledge both large-scale overviews in assessing gene variants as drug targets in industry work, while “deep phenotyping” would subject individuals with the variant to much closer scrutiny. Garret tries to imagine what these developments would do to animal studies on manufactured and inbred “model” strains. Maybe, he seems to suggest, the only way to confidently predict the human condition is to use humans to predict it. “A true big-picture systems biology approach to discovery is feasible and can be facilitated by techniques that provide the quantity and quality of data required to enable physiological measurements at scale” ^{3, p. 553}

Human phenomic science could pave the way toward answering questions now unanswerable regarding unanticipated drug reactions or distinguishing between patients with varied syndromes of pain. It might clarify inter-individual differences in responses to drug or environmental instigations. Certainly, the implications for drug development and safety testing are legion. “If we want to move from the detection of large average effects of therapies to a more precise approach to medicine, then we ought to  consider a strategic effort to recruit investigators and develop infrastructures to further support human phenomic science” ^{3, p. 553}

Finally, the 2023 paper “The Circadian Biology of Heart Failure” in Circulation Research follows up his and co-authors’ conceptual presentation of “Molecular Clocks and the Human Condition” with detailed data on molecular clocks’ influence on congestive heart failure. The paper summarizes what is now known about the cardiac clocks that influence the life cycle of CHF and reviews the genetic contributions that control them. Cardiac circadian and diurnal oscillations that influence contractility, metabolism, remodeling and response to injury, electrophysiology, neurohumoral function and the kidney, and chronotherapy are taken up one by one.

We see Garret returning in 2023 to what was a conceptual vision in 2015 with now well-substantiated data to support his predictions. He would probably say that this is how science works—from either an inspired creative revelation or an accident:

FG: "Sometimes we go looking for things and other times we stumble across them."

RC: "Yes, but do you think the stumbling is really just coincidence or are you looking for the thing that [you imagine] is there?"

FG: "I think it’s probably a mixture. I think I wouldn’t underestimate the stumble. Recognizing when you do stumble across something that’s important—that’s the trick."

Were we to fully take stock of the singular constituents in FitzGerald’s inquiry, we would better teach the young, critique current concepts, and clear paths toward the unknown. This much he makes clear: Ideas do not spring from nowhere. Thinkers do not think alone. Short views of the future are tethered to the present, while long views of the future escape the now. Speculation is a gift or a hard-won prize. Mind/brain/consciousness/imagination is a high-level summit meeting of powerful concepts, knowledge, and desires. Combining unlike things unusually is the pinnacle of thought.

As I listened to Garret describe his wide-ranging research on molecular clocks, translational research, and the birth of human phenotypic science, he took pains to impress on me the power these ideas exert on current understandings of human biology. He prefaced his description of his interest in molecular clocks with these words:

FG: "As we get older particularly, the center does not hold and things fall apart."

Garret borrows these words from the Irish poet W.B. Yeats in his poem “The Second Coming,” written in 1919 as the Treaty of Versailles ended the Great War.[i] Yeats was mourning the deaths and destruction of the war while realizing that the world order had changed. It was no longer what it had been before the trenches, before the unthinkable destruction of W.W. I. Yeats cast the scene in global terms and intimate terms at once. Here is the poem’s first of two stanzas:

Turning and turning in the widening gyre   

The falcon cannot hear the falconer;

Things fall apart; the centre cannot hold;

Mere anarchy is loosed upon the world,

The blood-dimmed tide is loosed, and everywhere   

The ceremony of innocence is drowned;

The best lack all conviction, while the worst   

Are full of passionate intensity.

By choosing these particular words to describe the challenges facing his molecular clocks, and by extension his other discoveries, Garret conveys the clocks’ elemental powers. Yeats’s falcon has escaped control of its master—things are not just adrift but are falling apart. By line 4, anarchy is loosed upon the world. Garret borrows this harrowing language to express the magnitude he now ascribes to the failure of synchronization of the temporal controls he and his lab have found in tissues outside of the brain. The same could be said about the possible failures of translational science or human phenotypic science.

I asked Garret how he developed his fluency in literature and philosophical thinking. Growing up in Ireland, he was permitted to choose 6 or 7 majors for his college education. Whether or not he knew as a high-school senior that he would become a cellular biologist, he chose French, English, and the Classics. Looking back now, he realizes this choice gave him "a breadth of experience in other things. They were really what kept you sane as you persisted through training in medicine and science. They became your intellectual recreation that did much to inform the way you did your science or indeed the way you treated patients. Particularly Classics had a big influence. Classics really shaped my approach to life in a way that far exceeded what I expected."

Garret’s chance quotation of an Irish master poet during our interview hints of the world view of our colleague who found his inspiration from literature and the Classics. Reading Plato, Homer, Sophocles, Euripides, Aristotle, and the Stoics submerged him in realms of moral ambiguity, individual self-emergence within conflict-laced situations, and methods of thinking through contradictions and uncertainties. Reading his beloved Irish poets and novelists not only provides him with the cultural foundations of life as an Irish citizen but, I suggest, inflects his science with the vision and ethical insight displayed in his repeated accomplishments of foreseeing and then moving toward a future.

We take from this visit with a master a focus on persistence and humility and a realization of the temporal in health and illness, in science and life. He has given us a model of patience, method, and collaborative practice across altogether unlike disciplines and questions. We leave this experience with Garret FitzGerald with rekindled optimism for the power of the sciences to improve the health of the public and to unveil to us their beauty. Toward the end of this interview, Garret recites a thought from Machiavelli’s The Prince about responses to innovation:

"There’s a great quote from The Prince in which he talks about the reluctance of people to accept a new order of things. So many people have on the one hand a clear benefit in accepting the existing order of things. And even to those who may be convinced by new information, it's uncertain as to how they will benefit from the emergence of a new order of things."

Here is the whole citation, which Garret has pinned over his desk:

It ought to be remembered that there is nothing more difficult to take in hand, more perilous to conduct, or more uncertain in its success, than to take the lead in the introduction of a new order of things. Because the innovator has for enemies all those who have done well under the old conditions, and lukewarm defenders in those who may do well under the new. This coolness arises partly from fear of the opponents, who have the laws on their side, and partly from the incredulity of men, who do not readily believe in new things until they have had a long experience of them. [6]

Garret discovers and innovates and braves new paths for science, humbly trusting that some, at least, will listen. We wait with great impatience to hear his next transformational story.