Healthcare analytics, AI solutions for biological big data, providing an AI platform for the biotech, life sciences, medical and pharmaceutical industries, as well as for related technological approaches, i.e., curation and text analysis with machine learning and other activities related to AI applications to these industries.
Cancer Surgery Rethought: Immunotherapy Takes the Lead
Curator: Dr. Sudipta Saha, Ph.D.
In a recent phase 2 study published in The New England Journal of Medicine, the efficacy of nonoperative management was assessed in patients with mismatch repair–deficient (dMMR) solid tumors. Instead of undergoing curative-intent surgery, patients with stage I to III dMMR tumors were administered immune checkpoint inhibitors.
The study was conducted across two cohorts involving 117 patients. After two years of follow-up, a recurrence-free survival rate of 92% (95% CI, 86 to 99) was achieved. It was found that complete clinical responses could be maintained without surgical intervention, and substantial preservation of organ function was observed.
The avoidance of surgery was associated with fewer treatment-related complications and a significant improvement in patients’ quality of life. It has been emphasized that dMMR tumors, being highly immunogenic, respond exceptionally well to immune checkpoint blockade, thereby offering a viable alternative to conventional surgery-based treatment plans.
While the study’s findings have been considered ground breaking, long-term data have been recommended to fully validate this approach. Future studies are expected to refine patient selection criteria and monitoring strategies to ensure sustained outcomes.
Overall, a potential shift in the standard of care for patients with early-stage dMMR tumors has been proposed, highlighting how personalized immunotherapy can redefine oncological practice.
Resitu Medical Sets Stage for Breakthrough in Breast Tumour Removal
Curator: Dr. Sudipta Saha, Ph.D.
Resitu Medical, a Swedish company specializing in minimally invasive breast tumour removal, has announced the appointment of Stefan Sowa as its new Chief Executive Officer. Strategic leadership is being strengthened as the company moves towards commercialization in both European and American markets.
A novel electrosurgical device, designed to excise entire breast lesions during the biopsy procedure, is being developed by Resitu. The device is intended to minimize the need for open surgery by allowing intact removal of tissue with minimal bleeding, guided by real-time ultrasound imaging. Preclinical studies are currently being conducted, and preparations for FDA clearance and CE marking are underway.
ISO 13485 certification for the design, development, manufacturing, and sales of the device has been successfully obtained. Investment has been secured from major shareholders, including Novoaim, ALMI Invest Stockholm, and STOAF, to support the finalization of the product and the initiation of serial production for clinical trials.
Through the use of its technology, false negatives are hoped to be reduced, while patient outcomes and diagnostic accuracy are expected to be significantly improved. The burden on healthcare systems may also be alleviated by minimizing the need for recalls and secondary biopsies.
Positive attention has been garnered at major medical conferences, with workshops hosted at events such as the Uppsala Breast Meeting, and favourable media coverage has been achieved. With Stefan Sowa at the helm, Resitu’s innovative device is poised to transform breast cancer management practices globally.
SNU-BioTalk 2025: Symphony of Cellular Signals in Metabolism and Immune Response – International Conference at Sister Nivedita University, Kolkata, India on 16 & 17 January 2025
Joint Convenor: Dr. Sudipta Saha (Member of LPBI since 2012)
About the Conference:
The International Conference on ‘Symphony of Cellular Signals in Metabolism and Immune Response’ focuses on the complex signalling pathways governing cellular functions in health and disease. It will explore the cellular mechanisms that regulate metabolism, immune responses, and survival, highlighting advances in medical science and biotechnology. Bringing together leading experts and emerging researchers, the conference will feature keynote lectures, panel discussions, research presentations, and interactive sessions, all designed to foster collaboration and innovation. By promoting an exchange of ideas, the event aims to drive transformative insights and solutions that impact human health and sustainable healthcare practices.
The conference will also be livestreamed on YouTube and Facebook
This programme will also host I-STEM: Indian Science, Technology and Engineering facilities Map (I-STEM) is a dynamic and interactive national portal for research cooperation.
Thrust areas:
Intracellular signalling processes of cellular metabolism
Signalling pathways in physiological and pathological processes
Studies are showing that genetic tests are being ordered at a sufficient rate however it appears there are problems in interpretation and developing treatment plans based on omics testing results
30 % of patients in past and now currently half of all patients are not being given the proper treatment based on genomic testing results (ASCO)
E.g. only 1.5% with NTRK fusions received a NTRK based therapy (this was > 4000 patients receiving wrong therapy)
A lung oncologist may only see one patient with NTRK fusion in three years
Precision Medicine Practice Gaps
48% of oncologist surveyed agreed pathologist needs to be more informed and relevant in the decision making process with regard to tests needing to be ordered
95% said need to flip cost issues ; what does it cost not to get a test … i.e. what is the cost of the wrong therapy
We need a new commercialization model for therapeutic development for this new era of “n of one” patient
There are some tumor markers approved by FDA that cant just be measured by NGS and are correlated with a pathologic complete response
Many point mutations will have no actionable drug
Many alterations are post-genomic meaning there is a post translational component to many prognostic biomarkers
Prevalence of point mutation with no actionable mutation is a limit of NGS
It is important to look at phospho protein spectrum as a potential biomarker
Reverse phase protein proteomic analysis
Made into CLIA based array
They trained centers around the US on the technology and analysis
Basing proteomics or protein markers by traditional IHC requires much antibody validation so if the mass spectrometry field can catch up it would be very powerful
With multiple MRM.MS there is too low abundance of phosphoproteins to allow for good detection
They conducted the I-SPY2 trial for breast cancer and determining if phosphoproteins could be a good biomarker panel
They found they could predict a HER2 response better than NGS
There were patients who were predicted HER2 negative that actually had an activated HER2 signaling pathway by proteomics so NGS must have had a series of false negatives
HER2 co phosphorylation predicts pathologic complete response and predicts therapy by herceptin
They found patients classified as HER2 negative by FISH were HER2 positive by proteomics and had HER2 activation
Amanda Paulovich, Professor, Aven Foundation Endowed Chair
Fred Hutchinson Cancer Center
Susan Monarezm Deputy Director ARPA-H
Henry Rodriguez, NCI/NIH
Eric Schadt, Pathos
Ezra Cohen, Tempus
Jennifer Leib, Innovation Policy Solutions
Nick Seddon, Optum Genomics
Giselle Sholler, Penn State Hershey Children’s Hospital
Janet Woodcock, formerly FDA
Amanda Paulovich: Frustrated by the variability in cancer therapy results. Decided to help improve cancer diagnostics
We have plateaued on relying on single gene single protein companion diagnostics
She considers that regulatory, economic, and cultural factors are hindering the innovation and resulting in the science way ahead of the clinical aspect of diagnostics
Diagnostic research is not as well funded as drug discovery
Biomarkers, the foundation for the new personalized medicine, should be at forefront Read the Tipping Point by Malcolm Gladwell
FDA is constrained by statutory mandates
Eric Schadt
Pathos
Multiple companies trying to chase different components of precision medicine strategy including all the one involved in AI
He is helping companies creating those mindmaps, knowledge graphs, and create more predictive systems
Population screening into population groups will be using high dimensional genomic data to determine risk in various population groups however 60% of genomic data has no reported ancestry
He founded Sema4 but many of these companies are losing $$ on these genomic diagnostics
So the market is not monetizing properly
Barriers to progress: arbitrary evidence thresholds for payers, big variation across health care system, regulatory framework
Beat Childhood Cancer Consortium Giselle
Consortium of university doctors in pediatrics
They had a molecular tumor board to look at the omics data
Showed example of choroid plexus tumor success with multi precision meds vs std chemo
Challenges: understanding differences in genomics test (WES, NGS, transcriptome etc.
Precision medicine needs to be incorporated in med education.. Fellowships.. Residency
She spends hours with the insurance companies providing more and more evidence to justify reimbursements
She says getting that evidence is a challenged; biomedical information needs to be better CURATED
Dr. Ezra Cohen, Tempest
HPV head and neck cancer, good prognosis, can use cituximab and radiation
$2 billion investment at Templest of AI driven algorithm to integrate all omics; used LLM models too
Dr. Janet Woodcock
Our theoretical problem with precision and personalized medicine is that we are trained to think of the average patient
ISPAT II trial a baysian trial; COVID was a platform trial
She said there should there be NIH sponsored trials on adaptive biomarker platform trials
This event will be covered by the LPBI Group on Twitter. Follow on
Real Time Coverage Morning Session on Precision Oncology: Advancing Precision Medicine Annual Conference, Philadelphia PA November 1 2024
Reporter: Stephen J. Williams, Ph.D.
Notes from Precision Medicine for Rare Diseases 9:00AM – 10:50
Precision Medicine and markers Cure models vs disease models Dr Ekker from UT MD Anderson
UT MD Anderson zebrafish disease model program now focusing more on figuring the mechanisms by which a disease model is reverted to normal upon CRISPR screens
Traditional drug development process long and expensive
2nd in class only takes 4 years while 3rd in class drugs take only 1.5 years
Health-in-a-fish: using a CRE system to go from disease to normal
The theory is making a CRE or CURE avatar; taking a diseased zebrafish and reverse engineering the disease genome
He used transposon based CRE mutational mutants with protein trap and 3’ exon trap (transposon based mutagenesis)
He reverted the diseased gene by CRE
He feels that can scale up to using organoids to develop more cure based models
FDA Christine Nguyen MD regulatory perspective of framework of drug approval for rare diseases
1 in 10 Amercians have rare diseases; 70% genetic and half are children
Due to Orphan Drug Act in 2023 half of novel drugs approved for rare diseases
CDER and FDA 550 unique drugs for over 1000 rare diseases
Clinical and surrogate validated endpoints are important for traditional approvals
For accelerated approval need predictive surrogate endpoint of clinical benefit
For accelerated approval needs completion of a confirmatory trials so FDA has new authority under FDORA; FDA can dictate trial milestones
Candidate surrogate endpoints: known to predict (validated) for traditional approval but reasonably likely to predict for accelerated approval
Does surrogate endpoint associated with a causal pathway? Also important to understand the magnitude of benefit so surrogate should be quantitative not just qualitative
RDEA is a series of 3 public workshops at FY2027 to promote innovation and novel endpoints and guidance
Frank Sasinowski FDA regulatory flexibility beyond One Positive Adequate and Well Controlled Trial
As we move to rare diseases we may only have one well controlled study so FDA feels we need new regulatory frameworks and guidelines especially for rare disease clinical trails especially with precision medicine
Accelerated approval does not mean your evidence is any less stringent that traditional approval (only difference is endpoint but quality of evidence the same)
Confirmatory evidence is a primary concern
In 2021 FDA coordinated with the two divisions CBER and CDER
Sometimes a primary endpoint shows positive benefit but secondary endpoints may not; FDA now feels that results from one well designed AWC gives confirmatory evidence
FDA can be flexible by taking in consideration the quantity and quality of confirmatory evidence and the totality of evidence
So pharmacology studies, natural history etc. can be enough
For a drug like Lamzede for mannosidosis there were no positive endpoint studies or for ADA SCID disease there was other compelling evidence
The FDA does have flexibility when it comes to advanced precision medicines and ultr rare diseases
10:50 Do we Really Need Liquid Biopsy? A Panel Discussion on the Issues Hampering the full Adoption of Liquid Biopsy
In Mexico leading cancer is colorectal but only have the FIT test and noone except one organization who issupplying health access
Access to precision medicine is a concern: the communication between the patient, who is pushing this more than healthcare, needs to be coordinated better with all stakeholders in care
We also need to educate many physicians even oncologists (like in Virginia) a better understanding of genetics and omics
FT3 consortium does testing to therapy (multistakeholder group comprised of patient advocacy groups); focus on amplifying global efforts to increase access; they are trying to make a roadmap to help access in other countries; when it comes to precision medicine it is usually the nurses that are aksing for training because they are usually the first responders for the patient’s questions
In rural areas just getting access to liquid biopsy is a concern and maybe satellite sites might be useful because the time to schedule is getting worse (like 3 or more months)
A recent paper showed that liquid biopsy may actually perpetuate health disparities and not ameliorate them
BloodPAC: there are barriers to LB access and adoption so consortium felt that there were many areas that need to be addressed: financial, access, disparities, education
ctDNA to define variants was the past focus; there is growing realization that there are representatives populations in your R&D studies
Submission of data to BloodPac is easier to do for tissue not for liquid biopsy; there is lack of harmonization across many of these databanks
Reimbursement: is a barrier to access for liquid biopsy
Illumina: challenge finding clinical utility for payers; FDA approval is not as hard; show improved outcomes for patients; Medicare is starting to approve some tests but the criteria bar keeps changing with payers;
How do we leverage the on-market data to support performance of your diagnostic test or genomic panel
This event will be covered by the LPBI Group on Twitter. Follow on
The Advancing Precision Medicine (APM) Annual Conference 2024 will take place at the Pennsylvania Convention Center in Philadelphia, November 1-2, 2024. Located in the heart of the biopharma ecosystem and with easy access to some of the most renowned academic and research institutions in the world, the APM Annual Conference 2024 will attract all segments of the precision medicine landscape.
The event will consist of two parallel tracks composed of keynote addresses, panel discussions and fireside chats which will encourage audience participation. Over the course of the two-day event leaders from industry, healthcare, regulatory bodies, academia and other pertinent stakeholders will share an intriguing and broad scope of content.
his event will consist of three immersive tracks, each crafted to explore the multifaceted dimensions of precision medicine. Delve into Precision Oncology, where groundbreaking advancements are reshaping the landscape of cancer diagnosis and treatment. Traverse the boundaries of Precision Medicine Outside of Oncology, as we probe into the intricate interplay of genetics, lifestyle, and environment across a spectrum of diseases and conditions including rare disease, cardiology, ophthalmology, and neurodegenerative disease. Immerse yourself in AI for Precision Medicine, where cutting-edge technologies are revolutionizing diagnostics, therapeutics, and patient care. Additionally, explore the emerging frontiers of Spatial Biology and Mult-Omics, where integrated approaches are unraveling the complexities of biological systems with unprecedented depth and precision.
Whether you are a seasoned researcher, a dedicated clinician, or a visionary industry professional, this conference serves as a vibrant hub of knowledge exchange, collaboration, and innovation. Elevate your expertise, expand your network, and chart the course of your career trajectory amidst a community of like-minded individuals. Join us as we embark on this transformative journey, where the possibilities are as limitless as the potential of precision medicine itself.
Powerful Cancer-Fighting Foods and Their Role in Body Repair
Curator: Dr. Sudipta Saha, Ph.D.
In the search for dietary approaches to prevent and fight cancer, certain foods have been found to possess potent anti-cancer properties. These foods not only help reduce the risk of cancer but also assist in repairing the body. Five such foods are green tea, broccoli like vetables, papaya, purple potatoes, and pomegranate—and the bioactive compounds responsible for their benefits.
1. Green Tea
Green tea, particularly rich in the catechin epigallocatechin gallate (EGCG), has gained considerable attention for its cancer-fighting properties. EGCG functions as a potent antioxidant, neutralizing free radicals and reducing oxidative stress, which is a key factor in the development of cancer. Studies suggest that EGCG can inhibit cancer cell proliferation by disrupting the signaling pathways essential for cell growth and survival, especially in breast, prostate, and colorectal cancers. Additionally, green tea has been shown to enhance the body’s immune function, making it more effective at targeting abnormal cells. EGCG induces apoptosis (programmed cell death) in cancer cells, halts angiogenesis (the formation of new blood vessels that nourish tumors), and inhibits metastasis (the spread of cancer cells to other parts of the body).
2. Broccoli and Cauliflower
Cruciferous vegetables like broccoli and cauliflower are rich in sulforaphane, a compound known for its detoxifying and anti-carcinogenic properties. Sulforaphane activates the body’s natural detoxification enzymes, which help eliminate carcinogens before they can damage cells. Moreover, it has been shown to inhibit the growth of various cancer cells, including those of the colon, breast, and prostate. Sulforaphane enhances the activity of phase II detoxification enzymes and induces apoptosis in cancer cells. It also inhibits histone deacetylase, an enzyme associated with cancer cell growth, thus preventing cancerous cells from replicating.
3. Papaya
Papaya is rich in carotenoids such as beta-carotene, lycopene, and beta-cryptoxanthin, which are powerful antioxidants. These compounds neutralize free radicals, reducing oxidative stress that can lead to cancer. Lycopene, in particular, has been linked to a lower risk of cancers, including those of the prostate, breast, and lung. Papaya also contains other bioactive compounds that help modulate immune responses, supporting the body’s ability to identify and destroy cancer cells. Carotenoids act by scavenging free radicals and reducing oxidative stress. Lycopene has also been shown to regulate cell cycle progression and inhibit growth factor signaling in cancer cells.
4. Purple Potatoes
Purple potatoes are unique due to their high levels of anthocyanins, which not only provide them with their distinctive color but also contribute to cancer prevention. Studies suggest that anthocyanins in purple potatoes help repair damaged tissues by promoting stem cell regeneration. They also have anti-inflammatory and anti-proliferative effects, which are crucial for halting cancer growth. Anthocyanins inhibit the growth of cancer cells by inducing cell cycle arrest and promoting the repair of damaged tissues through stem cell activation.
5. Pomegranate
Pomegranates are rich in ellagitannins, compounds that break down into ellagic acid in the body. Ellagic acid has been shown to possess anti-cancer properties by inhibiting tumor growth and promoting apoptosis in cancer cells. Pomegranate juice has demonstrated potential in reducing the progression of cancers such as breast and prostate cancer, due to its ability to suppress inflammation and oxidative stress. Ellagitannins and their metabolites inhibit cell proliferation and induce apoptosis. They also act by reducing inflammation and inhibiting the pathways involved in cancer cell survival and growth.
Conclusion
Incorporating foods like green tea, broccoli, papaya, purple potatoes, and pomegranates into your diet may help fight cancer and promote the repair of damaged tissues. The bioactive compounds found in these foods—EGCG, sulforaphane, carotenoids, anthocyanins, and ellagitannins—work through various mechanisms to inhibit cancer cell growth, induce apoptosis, and support the body’s natural repair processes. Including these nutrient-dense foods in your diet may contribute to overall health and resilience against cancer.
2024 Nobel Prize in Physiology or Medicine jointly to Victor Ambros and Gary Ruvkun for the discovery of microRNA and its role in post-transcriptional gene regulation
Reporter: Aviva Lev-Ari, PhD, RN
Updated 10/22/2024
The revolution in our understanding of transcriptional regulation and dark regions of the genome
The genome of higher eukaryotes are comprised of multiple exonic and intronic regions, with coding and noncoding DNA respectively. Much of the DNA sequence between exonic regions of genes, the sequences encoding the amino acids of a polypeptide, was considered either promoter regions regulating an exonic sequence or ‘junk DNA’, which had merely separated exons and their regulatory elements. It was not considered that this dark DNA or junk DNA was important in regulating transcription of genes. It was felt that most gene regulation occurred in promoter regions by response element factors which bound to specific sequences within these regions.
MicroRNA (miRNA), originally discovered in Caenorhabditis elegans, is found in most eukaryotes, including humans [1–3]. It is predicted that miRNA account for 1-5% of the human genome and regulate at least 30% of protein-coding genes [4–8]. To date, 940 distinct miRNAs molecules have been identified within the human genome [9–12] (http://microrna.sanger.ac.uk accessed July 20, 2010). Although little is currently known about the specific targets and biological functions of miRNA molecules thus far, it is evident that miRNA plays a crucial role in the regulation of gene expression controlling diverse cellular and metabolic pathways.
MiRNA are small, evolutionary conserved, single-stranded, non-coding RNA molecules that bind target mRNA to prevent protein production by one of two distinct mechanisms. Mature miRNA is generated through two-step cleavage of primary miRNA (pri-miRNA), which incorporates into the effector complex RNA-induced silencing complex (RISC). The miRNA functions as a guide by base-pairing with target mRNA to negatively regulate its expression. The level of complementarity between the guide and mRNA target determines which silencing mechanism will be employed; cleavage of target messenger RNA (mRNA) with subsequent degradation or translation inhibition
Fig. (1). MicroRNA maturation and function.
Figure. miRNA maturation and function. Source: Macfarlane LA, Murphy PR. MicroRNA: Biogenesis, Function and Role in Cancer. Curr Genomics. 2010 Nov;11(7):537-61. doi: 10.2174/138920210793175895.
The following is an interview in the journal Journal of Cellular Biology with Dr, Victor Ambros on his discovery of miRNA.
Source: Ambros V. Victor Ambros: the broad scope of microRNAs. Interview by Caitlin Sedwick. J Cell Biol. 2013 May 13;201(4):492-3. doi: 10.1083/jcb.2014pi. PMID: 23671307; PMCID: PMC3653358.
Once, we thought we understood all there was to know about how gene expression is regulated: A cell can tinker with the expression level of a given protein’s messenger RNA by modifying the activity, abundance, and type of transcription factors in the nucleus or with the RNA’s stability once it is made. But then came a surprising story about a short RNA in C. elegans called lin-4, which didn’t encode a protein but prevented expression of the protein encoded by another gene, lin-14, through antisense binding to lin-14 mRNA (1, 2). Today, we know that lin-4 was just the first example of a large number of small RNAs, called microRNAs, which regulate the expression of various other proteins in a similar way.
Victor Ambros, whose lab published that first story about lin-4, has been studying microRNAs (3, 4) and their regulation (5, 6) ever since, pushing forward our understanding of this powerful mechanism. We called him at his office at the University of Massachusetts Medical School to get some perspective on microRNAs and his career and to learn about some of the latest developments in his lab.
“That shared discovery is one of the most precious moments in my career.”
FROM FARM TO LAB TABLE
How did you end up doing a PhD with David Baltimore?
I was the first scientist in my family. My dad was an immigrant from Poland. He came to the States just after World War II and met my mom. They got married, moved to a farm in Vermont, and started farming. My siblings and I grew up amongst the cows and pigs and helped with the haying and cutting corn, stuff like that.
When I was about nine, I got interested in science, and after that I always wanted to be a scientist. I was an amateur astronomer; I built a telescope and started to imagine that I could actually do astronomy or physics as an occupation. But I quickly changed my mind when I reached college, in part because I realized that my math skills weren’t really up to the task of being a physicist and also because I discovered molecular biology and genetics and just fell in love with both subjects. David taught one of the advanced biology classes I took as an undergraduate at MIT, and that probably had some influence on my decision to work with him. After college, I worked as a technician in David’s lab for a year. I liked it a lot and stayed on in his lab when I entered graduate school at MIT. I was lucky because I had gotten a little bit of traction on a project and continued on that as a grad student, so I ended up finishing grad school fairly efficiently.
Had you any idea at the time what the nature of the lin-4 mutant was?
The assumption was that it was a protein product. I mean, nobody ever thought that there would be any other kind of regulator. There really wasn’t any reason to imagine that there were any other kinds of molecules necessary, other than proteins, to carry out everything that’s done in a cell—especially with regard to the regulation of gene expression. The complexity of gene regulation by proteins alone was so enormous that I never imagined—and nobody I knew imagined—that we needed to look for new kinds of regulatory molecules. The realization that lin-4 was antisense to the 3′-untranslated region of lin-14 was totally the result of communication between Gary and me. That shared discovery is one of the most precious moments in my career. But at the time I didn’t realize that this might be the first example of a general mechanism for regulating gene expression because I was prone to thinking that whatever I was studying in the worm was not generally applicable. It wasn’t until genome sequences were made available that the prevalence of this mechanism became clear.
THE RIGHT CONTEXT
You’ve moved to studying processes that modulate microRNA function…
One protein we’ve studied is called Nhl-2. It’s an example of an emerging class of proteins that can modulate, positively or negatively, the RNA-induced silencing complex (RISC) that inhibits mRNAs targeted by microRNAs. This class of genes may have either general effects on RISC activity or, in some cases, more specific effects. One area of interest in the lab right now is trying to understand the specific outcomes for the regulation of particular microRNAs. Do they always interact with all their targets, or is their activity on some targets promoted or inhibited at the expense of other targets? Can their interaction with certain targets be modified depending on context? We’re using genetic and genomic approaches to identify new modulatory cofactors.
Watch Video
Victor Ambros was born in 1953 in Hanover, New Hampshire, USA. He received his PhD from Massachusetts Institute of Technology (MIT), Cambridge, MA, in 1979 where he also did postdoctoral research 1979-1985. He became a Principal Investigator at Harvard University, Cambridge, MA in 1985. He was Professor at Dartmouth Medical School from 1992-2007 and he is now Silverman Professor of Natural Science at the University of Massachusetts Medical School, Worcester, MA.
Gary Ruvkun was born in Berkeley, California, USA in 1952. He received his PhD from Harvard University in 1982. He was a postdoctoral fellow at Massachusetts Institute of Technology (MIT), Cambridge, MA, 1982-1985. He became a Principal Investigator at Massachusetts General Hospital and Harvard Medical School in 1985, where he is now Professor of Genetics.
This year’s Nobel Prize honors two scientists for their discovery of a fundamental principle governing how gene activity is regulated.
The information stored within our chromosomes can be likened to an instruction manual for all cells in our body. Every cell contains the same chromosomes, so every cell contains exactly the same set of genes and exactly the same set of instructions. Yet, different cell types, such as muscle and nerve cells, have very distinct characteristics. How do these differences arise? The answer lies in gene regulation, which allows each cell to select only the relevant instructions. This ensures that only the correct set of genes is active in each cell type.
Victor Ambros and Gary Ruvkun were interested in how different cell types develop. They discovered microRNA, a new class of tiny RNA molecules that play a crucial role in gene regulation. Their groundbreaking discovery revealed a completely new principle of gene regulation that turned out to be essential for multicellular organisms, including humans. It is now known that the human genome codes for over one thousand microRNAs. Their surprising discovery revealed an entirely new dimension to gene regulation. MicroRNAs are proving to be fundamentally important for how organisms develop and function.
Ambros and Ruvkun were interested in genes that control the timing of activation of different genetic programs, ensuring that various cell types develop at the right time. They studied two mutant strains of worms, lin-4 and lin-14, that displayed defects in the timing of activation of genetic programs during development. The laureates wanted to identify the mutated genes and understand their function. Ambros had previously shown that the lin-4 gene appeared to be a negative regulator of the lin-14 gene. However, how the lin-14 activity was blocked was unknown. Ambros and Ruvkun were intrigued by these mutants and their potential relationship and set out to resolve these mysteries.
Ambros and Ruvkun performed further experiments showing that the lin-4 microRNA turns off lin-14 by binding to the complementary sequences in its mRNA, blocking the production of lin-14 protein. A new principle of gene regulation, mediated by a previously unknown type of RNA, microRNA, had been discovered! The results were published in 1993 in two articles in the journal Cell.
Ruvkun cloned let-7, a second gene encoding a microRNA. The gene is conserved in evolution, and it is now known that microRNA regulation is universal among multicellular organisms.
Andrew Z. Fire and Craig C. Mello, awarded the Nobel Prize in 2006, described RNA interference, where specific mRNA-molecules are inactivated by adding double-stranded RNA to cells.
Mutations in one of the proteins required for microRNA production result in the DICER1 syndrome, a rare but severe syndrome linked to cancer in various organs and tissues.
A large clinical trial has shown that pembrolizumab (Keytruda), an immunotherapy drug, nearly doubles the cancer-free survival time for patients with high-risk, muscle-invasive bladder cancer following surgery. The study, published on September 15, 2024, in The New England Journal of Medicine, was led by NIH researchers and demonstrated that pembrolizumab outperforms traditional observation methods post-surgery. Patients receiving pembrolizumab had a median cancer-free survival of 29.6 months, compared to 14.2 months for the observation group.
The trial enrolled 702 participants, some of whom had previously undergone cisplatin-based chemotherapy (neoadjuvant therapy). Pembrolizumab was administered every three weeks for a year. The drug was well tolerated, with common side effects including fatigue, itching, diarrhea, and thyroid issues.
Interestingly, the benefit of pembrolizumab was seen regardless of the tumor’s PD-L1 status.
Patients with PD-L1-positive tumors had a median cancer-free survival of 36.9 months.
Patients with PD-L1-negative tumors experienced 17.3 months cancer-free.
These results suggest that PD-L1 status should not be the sole factor in selecting patients for this therapy.
While overall survival rates were similar between the pembrolizumab and observation groups, many patients in the observation group began taking nivolumab once it was approved, complicating survival comparisons. Researchers are continuing to explore other treatment combinations and biomarkers to better personalize adjuvant therapy for bladder cancer patients.
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