We live in a time where the rate of medical and superlative scientific advances is accelerating by more than 1,300% since 1985, according to one recent estimate. With so many unprecedented, transformative breakthroughs happening, forecasting which one will be awarded top research honors isnt getting any easier. But with the naming of this years Nobels fast approaching the medicine award will be announced on Oct. 3, physics on Oct. 4, chemistry on Oct. 5 prize prognosticating for the World Series of Science is once again in full swing.

Public polls, tallies of other elite awards, and journal citations have helped betting-minded people collect the names of whos most likely in the running. The shortlist includes researchers who elucidated how cells make energy, those who discovered the chemical chatter of bacteria, many of the brilliant minds who shepherded us into the era of the genome, and most prominently, the pioneers behind the mRNA Covid vaccines.

How Nobels are decided is a matter of grave secrecy records of who nominated and voted for whom are sealed for 50 years making forecasting new winners even more of a challenge. Still, some experts have developed systems that do a decent job.

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David Pendlebury of Clarivate looks at how often a scientists key papers are cited by peers and awarded so-called predictive prizes like the Lasker or Gairdner awards. Each year he comes up with a group of Citation Laureates, and since 2002, 64 of his picks have gone on to receive a Nobel Prize.

Using that strategy, Pendlebury thinks the medicine Nobel could go to the researchers who discovered that different kinds of malformed protein aggregates, in different cell types, underlie a number of neurological diseases including Parkinsons, ALS, and frontotemporal dementia. Virginia Man-Yee Lee of the University of Pennsylvania published a seminal Science paper in 2006, which has now been cited more than 4,000 times. When Pendlebury dug into those citations, he noticed that researchers almost always mentioned that paper in tandem with a very similar but much lower-profile study published a few months later by Masato Hasegawa of the Tokyo Metropolitan Institute of Medical Science.

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This phenomenon of simultaneous independent discovery is very common in science, more than I think people understand, Pendlebury told STAT. So the citations tend to go to the first mover, but they are really a pair. And since their papers, the field has blossomed in many directions, because it was a big step forward for trying to find therapies for these kinds of diseases.

For similar reasons, Pendlebury also has his eyes on two scientists who made groundbreaking discoveries about the genetic basis of disease: Mary-Claire King of the University of Washington for uncovering the role of mutations in the BRCA genes in breast and ovarian cancers, which revolutionized cancer screening, and Stuart Orkin of Harvard Medical School for identifying the genetic changes behind the various types of thalassemia leading to promising new gene-based therapies for inherited blood disorders.

Another thing that Pendlebury takes into account in his predictions is periodicity. The committees tend to take turns rewarding different disciplines; neuroscience, cancer, or infectious-disease discoveries win every decade or so. For the medicine prize, periodicity also shows up between discoveries of basic molecular biology and ones that lead to people actually being treated or cured of the things that ail them.

In the past decade, the medicine prize has more times than not gone back to basics. In 2013, it went to intra-cell transportation, in 2016 to the process of cellular self-destruction, in 2017 to the genetic clocks that control circadian rhythms, in 2019 to how cells sense and adapt to oxygen availability, and last year to how cells sense temperature and touch. Prizes with a more clinical focus have been awarded in 2015, (roundworm and malaria therapy), 2018 (immuno-oncolgy), and 2020 (hepatitis C).

Thats just one reason why cancer biologist Jason Sheltzer of the Yale School of Medicine is so bullish on this years medicine prize going to Katalin Karik of BioNTech and Drew Weissman of Penn Medicine for taking messenger RNA, or mRNA, on a 40-year journey from an obscure corner of cell biology to a pandemic-halting vaccine technology. Its such a radical change in vaccine technology, at this point billions of doses have been given, and it has incontrovertibly saved millions of people from dying of Covid, Sheltzer said. To me, its just a slam dunk.Sheltzer has been making Nobel predictions on Twitter since 2016 and correctly chose immuno-oncology pioneer James Allison for the 2018 medicine prize. His methodology is a bit more straightforward; he tracks winners of seven major science prizes the Horwitz, Wolf, Albany, Shaw, and Breakthrough Prize, in addition to the Lasker and Gairdner because the data show that theres only so long the Nobel Committee can ignore people whove won at least two. Karik and Weissman have won five of the six. Its not a question of if it will happen, its just a question of when, he said.

Hes less certain about the chemistry prize. Might David Allis of Rockefeller and Michael Grunstein of UCLA finally get the call to Stockholm? They discovered one way genes are activated through proteins called histones for which they shared a 2018 Lasker and a 2016 Gruber Prize in genetics. The control of gene expression, otherwise known as epigenetics, is a fundamental process in cell biology that researchers and industry are just beginning to harness to treat human disease. But the last time epigenetics got the Nobel nod was in 2006, with Roger Kornbergs win in chemistry for his work unlocking the molecular mystery of how RNA transcripts are assembled.

Its been nearly 20 years since that field has been recognized with a prize, so you could make the case that its very much due this year, said Sheltzer.

Thats even more true for DNA sequencing, which was last awarded a Nobel in 1980 to Wally Gilbert and Frederick Sanger for their work developing the first (eponymously named) method for determining the order of base pairs in nucleic acids. But so much has happened in the field since then, that the slate of worthy sequencing successors is practically overflowing.

Should it go to the scientists who gave us the first-ever draft of the human genome, and if so, which ones? Hundreds of researchers all over the world aided in the effort, which was a feat of engineering and mass production as much as scientific innovation. If the chemistry or medicine Nobel committees takes a cue from their physics counterpart, who in 2017 honored the organizers of the international project that discovered gravitational waves, then the top contenders would likely be the Human Genome Projects cat-herder-in-chief and recently departed director of the National Institutes of Health, Francis Collins, and Eric Lander, whose lab at the Broad Institute churned out much of the draft sequence. A third might be Craig Venter, whose competing private sequencing push at Celera raced the public effort to a hotly contested draw.

Perhaps a more deserving trio would be Marvin Caruthers of the University of Colorado, Leroy Hood of the Institute for Systems Biology, and Michael Hunkapiller, former CEO of DNA-sequencing behemoth Pacific Biosciences. They invented the technology behind the first automated sequencers, which powered the Human Genome Project (and were Pendleburys pick for the chemistry Nobel in 2019).

Or perhaps the call from Stockholm will go out to David Klenerman and Shankar Balasubramanian of the University of Cambridge, who developed the sequencing-by-synthesis technology that came after the Human Genome Project and is now the workhorse of the modern sequencing era (and for which they won the 2020 Millennium Technology Prize and this years Breakthrough Prize in life sciences). More recent inventions, like the nanopore sequencing technologies that have enabled the construction of the first actually complete human genomes in the last few years are also in the running, but probably a longer shot, despite their obvious contributions to both chemistry and medicine. Thats because the Nobel committees tend to tilt toward true trailblazers and away from those who extend an initial, foundation-laying discovery or insight.

The Human Genome Project, a perennial topic of conversation among Nobel-casters, has inspired even more intrigue than usual this year, following the surprise exit of Eric Lander from his position as White House science adviser in the wake of workplace bullying allegations.

Although the rare Nobel has been awarded to well-known jerks or kooks Kary Mullis, the eccentric inventor of PCR, and James Watson, the dubious co-discoverer of the double-helix structure of DNA (and frequent maker of racist, sexist remarks) come to mind the Royal Swedish Academy of Sciences, which selects the physics and chemistry laureates, and the Nobel Assembly at the Karolinska Institute, which chooses the physiology/medicine winner, tend to steer clear of controversy.

Its hard to find many examples of a Nobel being awarded to someone whos been super controversial, said Sheltzer.

Among Pendleburys picks, the person who skirts closest is perhaps Stephen Quake of Stanford University and the Chan Zuckerberg Initiative, who provided advice to He Jiankui, the Chinese scientist who created the worlds first CRISPR babies. Stanford later cleared Quake of any misconduct. Quake has made important discoveries in microfluidics which led to rapid advances in noninvasive testing and single cell sequencing, and Pendlebury sees him as a favorite for a physics Nobel.

In chemistry, Pendlebury likes another Stanford University engineer, Zhenan Bao, for her paradigm-shifting work in the field of semiconducting polymers making stretchable electronic skin. Hes also got his eye on Daniel Nocera at Harvard University for foundational work illuminating the proton-coupled electron transfer process that powers cells, and the team of Bonnie Bassler from Princeton University and E. Peter Greenberg of the University of Washington for their discovery of quorum sensing a chemical communication system between bacteria.

Besides citations, prediction prizes, and periodicity, Pendlebury is also playing the long game. I pay special attention to papers that are 15, 20, 25, 30 years old, because it usually takes a decade or two for research to be selected by the Nobel Prize Committee, he said.

That might complicate things for one of the leading vote-getters in an online poll for the chemistry Nobel John Jumper of the Alphabet-owned company DeepMind and a 2023 Breakthrough Prize in life sciences winner. His work leading the AlphaFold artificial intelligence program stunned the world two years ago by essentially solving one of biologys most enduring challenges: quickly and accurately predicting the 3D structure of a protein from its amino acid sequence.

Thats why this first-time Nobel forecaster is betting on another top vote-getter for the chemistry prize, Carolyn Bertozzi of Stanford University, who has spent much of her illustrious career devising methods to understand an elusive but critical class of sugar-coated molecules called glycans found on the surface of almost all living cells. Shes been a member of the National Academy of Sciences since 2005 and won the Wolf prize earlier this year, in recognition of founding the field of bioorthogonal chemistry a term Bertozzi coined two decades ago that refers to reactions scientists can perform within living organisms without interfering with their normal functions.

Sticking with dark-horse picks (because, why not), Im going with Yuk Ming Dennis Lo of the Chinese University of Hong Kong for the medicine prize. In 1997, he reported that a growing fetus sheds cell-free DNA into the mothers blood. Ten years later, he found a way to use that DNA to detect the signature abnormalities associated with Down syndrome. Together, these discoveries revolutionized clinical practice of screening for fetal genetic abnormalities, leading to the development of non-invasive prenatal testing now used by millions of people every year. Lo has only just begun to be recognized for that work, winning last years Breakthrough Prize for life sciences and this years Lasker Award for clinical medical research, which was announced on Wednesday. He also founded companies based on this same principle for the early detection of multiple cancers, one of which was acquired by pioneering liquid biopsy giant Grail.

Other crowdsourced efforts to predict Nobel winners arent making a return appearance, including the March Madness-style brackets run for many years by the scientific research honors society Sigma Xi. (Last year saw Bertozzi lose in the finals to Omar Yaghi and Makoto Fujita, pioneers of metal-organic self-assembling structures.) Sigma Xi couldnt be reached for comment, but the change comes amid increasingly loud criticism of the Nobel Prizes, for the way they distort the collaborative nature of the scientific enterprise and overlook many of its important contributors (including many women and people of color).

Even Nobel obsessives like Sheltzer admit those arguments are becoming more compelling. But he likes how, at least for a few days every October, he can count on scientific discoveries splashing across the front page of the New York Times and leading the hour on the nightly news. There are amazing things happening in the scientific world right now, like CRISPR gene editing and immunotherapy for cancer, that I think should really be front-page news much more frequently than they are, said Sheltzer. But Im glad that the Nobel Prize shines a spotlight on them and elevates them into the national consciousness, even if just for a brief period of time.

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Who will get the call from Stockholm? It's time for STAT's 2022 Nobel Prize predictions - STAT