Lindsay Burns

Lindsay H. Burns (born 1965) is an American neuroscientist and rower who won a silver medal at the 1996 Summer Olympics.[1] She is a senior vice president of the pharmaceutical company Cassava Sciences[2] and married to its CEO Remi Barbier.

Lindsay Burns
Personal information
Born1965 (age 57–58)
Big Timber, Montana, U.S.
Medal record
Women's rowing
Representing  United States
Olympic Games
Silver medal – second place 1996 Atlanta Lwt double sculls
World Rowing Championships
Gold medal – first place 1987 Copenhagen Lwt four
Silver medal – second place 1990 Tasmania Lwt double sculls
Silver medal – second place 1991 Vienna Lwt double sculls
Bronze medal – third place 1994 Indianapolis Lwt double sculls

As of July 2022, Cassava Sciences and papers published by Burns are under investigation; Cassava denies any wrongdoing.[3][4][5][6][7]

Personal life

Burns was born in 1965[8] and raised in Big Timber, Montana.[9] She graduated from Harvard University in 1987.[9] In 1991, she obtained a PhD in neuroscience from University of Cambridge[9] on a thesis titled Functional interactions of limbic afferents to the striatum and mesolimbic dopamine in reward-related processes,[10] which was supervised by Barry Everitt and Trevor Robbins.[11][12]

Burns worked as a research fellow in psychobiology at McLean Hospital in Belmont, Massachusetts.[9] She joined Cassava Sciences in 2002 and became senior vice president of neuroscience in 2021.[13]

Burns is married to Remi Barbier, the CEO and founder of Cassava Sciences.[14][15][16]

Rowing career

Burns started competitive rowing soon after entering Harvard.[9] In 1987, she rowed in the Radcliffe varsity crew and won the Eastern Association of Women's Rowing Colleges (EAWRC) championship that awarded her the Ivy title and the EAWRC League title.[14] She was part of the US rowing team from 1987 and from 1990–1996. Competing in the lightweight category at six World Rowing Championships, she won four medals: gold at the 1987; silvers in the double in 1990 and 1991; and bronze in the double in 1994. She won a silver medal at the 1995 Pan American Games competing in the quad sculls (heavyweight) category[1] and she won the European Rowing Championships at Lucerne in 1995 with Teresa Bell.[17] She was an alternate rower at the 1992 Summer Olympics in Barcelona, Spain.

She teamed up again with Teresa Bell at the 1996 Summer Olympics in Atlanta, United States, and won a silver medal in the Lightweight Double Sculls.[1] In 2006, she was inducted into the Harvard Sports Hall of Fame.[14] In 2016, she was inducted into the National Rowing Foundation Hall of Fame.[18]

Scientific works

Burns' first research was on the effect of neurokinin A on brain functions in rats. Her first paper in 1988, written with Ann E. Kelley, reported that neurokinin A in the ventral tegmental area modifies dopamine circuits to induce behavioral changes.[19] She continued her PhD research on the role of dopamine and the limbic system.[11][12][10][20][21] During her post-doc at McLean Hospital, she focused on neurodegenerative diseases, specifically, transplantation of pig neural cells into rat brain as a possible treatment of Parkinson's or Huntington's disease.[22] Further research indicated possible use in humans.[23] While working for a biotech company later acquired by Elan Pharmaceuticals, she published the effects of ziconotide in a rat model of spinal cord ischemia.[24]

In 2005, she published a series of papers on Oxytrex and related research with ultra-low doses of certain (opioid antagonists) to enhance analgesia and prevent opioid-induced hyperalgesia, opioid tolerance and substance dependence.[25][26][27][28]

Since 2006, Burns has collaborated with Hoau-Yan Wang at the City University of New York,[29] who had been investigating Alzheimer's disease. Previously identifying filamin A (FLNA) for its role in regulating opioid receptor signaling, Burns and Wang then identified FLNA as a critical protein in enabling Abeta42's signaling through the alpha 7 nicotinic acetylcholine receptor to induce Alzheimer's disease pathology.[30][31][32]

FLNA, simufilam and Alzheimer's disease

In 2008, Burns, Wang and Maya Frankfurt published in PLOS One a finding that the opioid antagonists naloxone and naltrexone bind with ultra-high affinity to FLNA to prevent mu opioid receptor excitatory signaling.[33] Burns and Wang identified the binding site on FLNA and the activation of CREB by opioid receptor - Gs coupling in the same journal the next year.[34] FLNA is a cytoplasmic protein that maintains normal cell shape and division. In 2010, Burns and Wang announced a novel analgesic" which they named PTI-609 (PTI for Pain Therapeutics, Inc., the former name of Cassava Sciences) and stated that the molecule binds to FLNA as well as activating mu opioid receptors.[35]

In 2012, they published in The Journal of Neuroscience a novel compound PTI-125 that binds to FLNA similarly to naloxone and naltrexone.[36] With PTI-125, they stated that FLNA aberrantly links to the alpha 7 nicotinic receptor, enabling signaling of Abeta42 to hyperphosphorylate tau.[31][36]

In 2017, they reported in Neurobiology of Aging that the FLNA in Alzheimer's disease transgenic mice and human postmortem brain tissue has an altered conformation (based on a shift in isoelectric focusing) and that PTI-125 binding to altered FLNA restores its normal shape, thereby reducing tau hyperphosphorylation, amyloid deposits and tau-containing lesions in the brains of the mice.[37][38] The United States Adopted Names (USAN) gave the drug name for PTI-125 as simufilam in 2020;[39] as of 2022, it is in Phase III clinical trials.

Research controversies
Further information: Cassava Sciences § Allegations of research fraud

As of July 2022, Cassava Sciences and papers published by Burns and Wang are under investigation by the U.S. Justice Department; Cassava denies any wrongdoing.[3][4][5] The U.S. Securities and Exchange Commission (SEC), the U.S. National Institutes of Health (NIH), and City University of New York (CUNY) were also investigating allegations of manipulated data.[5]

In October 2023, CUNY reported that they could obtain none of Wang's original data, which meant that they were unable to either prove or disprove allegations that the images were improperly manipulated.[40][41] According to The Wall Street Journal, the CUNY report stated that Burns shared with Wang some responsibility "for errors and misconduct".[41]

References
  1. "Biography: Lindsay Burns". Olympics. International Olympic Committee. Retrieved May 2, 2022.
  2. Keown, Alex (April 19, 2022). "Cassava Faces Renewed Speculation Over Experimental Alzheimer's Drug". BioSpace. Retrieved May 9, 2022.
  3. Taylor, Marisa; Spector, Mike (July 27, 2022). "Exclusive: Cassava Sciences faces U.S. criminal probe tied to Alzheimer's drug, sources say". Reuters. Retrieved July 31, 2022.
  4. "Cassava Sciences Responds to Media Reports" (Press release). Cassava Sciences. July 27, 2022. Retrieved August 16, 2022.
  5. Michaels, Dave; Walker, Joseph (November 17, 2021). "SEC Investigating Cassava Sciences, Developer of Experimental Alzheimer's Drug". Wall Street Journal. ISSN 0099-9660. Retrieved April 29, 2022.
  6. Mandavilli, Apoorva (April 18, 2022). "Scientists Question Data Behind an Experimental Alzheimer's Drug". The New York Times. ISSN 0362-4331. Retrieved April 28, 2022.
  7. "The Cassava Sciences saga: Short sellers, 'gaming' the FDA, and the damaging ripple effects".
  8. "Lindsay Burns". World Rowing.
  9. "Harvard at the Olympics". Harvard Magazine. Retrieved May 3, 2022.
  10. Burns, Lindsay H. (1991). Functional interactions of limbic afferents to the striatum and mesolimbic dopamine in reward-related processes (Ph.D. thesis). University of Cambridge. OCLC 556753196.
  11. Burns, L; Robbins, T; Everitt, B (1993). "Differential effects of excitotoxic lesions of the basolateral amygdala, ventral subiculum and medial prefrontal cortex on responding with conditioned reinforcement and locomotor activity potentiated by intra-accumbens infusions ofd-amphetamine". Behavioural Brain Research. 55 (2): 167–183. doi:10.1016/0166-4328(93)90113-5. PMID 8357526. S2CID 4032314.
  12. Burns, Lindsay H.; Everitt, Barry J.; Kelley, Ann E.; Robbins, Trevor W. (1994). "Glutamate-dopamine interactions in the ventral striatum: role in locomotor activity and responding with conditioned reinforcement". Psychopharmacology. 115 (4): 516–528. doi:10.1007/BF02245576. PMID 7871097. S2CID 28351013.
  13. "Lindsay H Burns, Cassava Sciences Inc: Profile and Biography". Bloomberg.com. Retrieved May 3, 2022.
  14. "Lindsay Burns Barbier '87". www.harvardvarsityclub.org. Retrieved May 2, 2022.
  15. Keefe, Patrick Radden (January 15, 2022). "Jordan Thomas's Army of Whistle-Blowers". The New Yorker. Archived from the original on July 22, 2022. Retrieved April 29, 2022.
  16. Feuerstein, Adam (April 5, 2022). "Troubles mount for Cassava Sciences, as patient enrollment lags for Alzheimer's drug studies". STAT. Retrieved April 30, 2022.
  17. "Rowing News". July 16–29, 1995.
  18. "The National Rowing Foundation Announces the 2016 Inductees to the National Rowing Hall of Fame". January 26, 2016.
  19. Burns, Lindsay H.; Kelley, Ann E. (1988). "Neurokinin-α injected into the ventral tegmental area elicits a dopamine-dependent behavioral activation in the rat". Pharmacology Biochemistry and Behavior. 31 (2): 255–263. doi:10.1016/0091-3057(88)90343-7. PMID 2469085. S2CID 20941335.
  20. Burns, Lindsay H.; Annett, Lucy; Kelly, Ann E.; Everitt, Barry J.; Robbins, Trevor W. (1996). "Effects of lesions to amygdala, ventral subiculum, medial prefrontal cortex, and nucleus accumbens on the reaction to novelty: Implications for limbic—striatal interactions". Behavioral Neuroscience. 110 (1): 60–73. doi:10.1037/0735-7044.110.1.60. ISSN 1939-0084. PMID 8652073.
  21. Parkinson, John A.; Olmstead, Mary C.; Burns, Lindsay H.; Robbins, Trevor W.; Everitt, Barry J. (1999). "Dissociation in Effects of Lesions of the Nucleus Accumbens Core and Shell on Appetitive Pavlovian Approach Behavior and the Potentiation of Conditioned Reinforcement and Locomotor Activity byd-Amphetamine". Journal of Neuroscience. 19 (6): 2401–2411. doi:10.1523/JNEUROSCI.19-06-02401.1999. PMC 6782569. PMID 10066290.
  22. Isacson, Ole; Deacon, Terrence W.; Pakzaban, Peyman; Galpern, Wendy R.; Dinsmore, Jonathan; Burns, Lindsay H. (1995). "Transplanted xenogeneic neural cells in neurodegenerative disease models exhibit remarkable axonal target specificity and distinct growth patterns of glial and axonal fibres". Nature Medicine. 1 (11): 1189–1194. doi:10.1038/nm1195-1189. PMID 7584993. S2CID 7344970.
  23. Galpern, Wendy R.; Burns, Lindsay H.; Deacon, Terrence W.; Dinsmore, Jonathan; Isacson, Ole (1996). "Xenotransplantation of Porcine Fetal Ventral Mesencephalon in a Rat Model of Parkinson's Disease: Functional Recovery and Graft Morphology". Experimental Neurology. 140 (1): 1–13. doi:10.1006/exnr.1996.0109. PMID 8682173. S2CID 23945411.
  24. Burns, Lindsay H.; Jin, Zhen; Bowersox, S.Scott (1999). "The neuroprotective effects of intrathecal administration of the selective N-type calcium channel blocker ziconotide in a rat model of spinal ischemia". Journal of Vascular Surgery. 30 (2): 334–343. doi:10.1016/S0741-5214(99)70145-X. PMID 10436454.
  25. Chindalore, Vishala L.; Craven, Richard A.; Yu, K. Peony; Butera, Peter G.; Burns, Lindsay H.; Friedmann, Nadav (2005). "Adding Ultralow-Dose Naltrexone to Oxycodone Enhances and Prolongs Analgesia: A Randomized, Controlled Trial of Oxytrex". The Journal of Pain. 6 (6): 392–399. doi:10.1016/j.jpain.2005.01.356. PMID 15943961.
  26. Olmstead, Mary C.; Burns, Lindsay H. (2005). "Ultra-low-dose naltrexone suppresses rewarding effects of opiates and aversive effects of opiate withdrawal in rats". Psychopharmacology. 181 (3): 576–581. doi:10.1007/s00213-005-0022-7. PMID 16010543. S2CID 13270740.
  27. Leri, Francesco; Burns, Lindsay H. (2005). "Ultra-low-dose naltrexone reduces the rewarding potency of oxycodone and relapse vulnerability in rats". Pharmacology Biochemistry and Behavior. 82 (2): 252–262. doi:10.1016/j.pbb.2005.08.008. PMID 16182352. S2CID 25513761.
  28. Burns, Lindsay H.; Vanderah, Todd W.; Wang, Hoau-Yan (2009), Dean, Reginald L.; Bilsky, Edward J.; Negus, S. Stevens (eds.), "Ultra-Low-Dose Opioid Antagonists Enhance Opioid Analgesia and Reduce Tolerance", Opiate Receptors and Antagonists, Totowa, NJ: Humana Press, pp. 3–17, doi:10.1007/978-1-59745-197-0_1, ISBN 978-1-58829-881-2, retrieved May 3, 2022
  29. Wang, Hoau-Yan; Burns, Lindsay H. (2006). "Gβγ that interacts with adenylyl cyclase in opioid tolerance originates from a Gs protein". Journal of Neurobiology. 66 (12): 1302–1310. doi:10.1002/neu.20286. PMID 16967511.
  30. Wang, Hoau-Yan; Bakshi, Kalindi; Frankfurt, Maya; Stucky, Andres; Goberdhan, Marissa; Shah, Sanket M.; Burns, Lindsay H. (2012). "Reducing Amyloid-Related Alzheimer's Disease Pathogenesis by a Small Molecule Targeting Filamin A". J Neurosci. 32 (29): 9773–9784. doi:10.1523/JNEUROSCI.0354-12.2012. PMC 6621293. PMID 22815492. S2CID 9933756.
  31. Burns, Lindsay H.; Wang, Hoau-Yan (2017). "Altered filamin A enables amyloid beta-induced tau hyperphosphorylation and neuroinflammation in Alzheimer's disease". Neuroimmunology and Neuroinflammation. 4 (12): 263–271. doi:10.20517/2347-8659.2017.50. PMC 8294116. PMID 34295950.
  32. Wang, Hoau‐Yan; Pei, Zhe; Xu, Qiang; Brunelle, Lynn A; Burns, Lindsay H.; Thornton, George Ben (2021). "SavaDx, a novel plasma biomarker to detect Alzheimer's disease, confirms mechanism of action of simufilam". Alzheimer's & Dementia. 17 (S5): online. doi:10.1002/alz.054385. S2CID 245570217.
  33. Wang, Hoau-Yan; Frankfurt, Maya; Burns, Lindsay H. (February 6, 2008). "High-affinity naloxone binding to filamin a prevents mu opioid receptor-Gs coupling underlying opioid tolerance and dependence". PLOS ONE. 3 (2): e1554. Bibcode:2008PLoSO...3.1554W. doi:10.1371/journal.pone.0001554. PMC 2212716. PMID 18253501.
  34. Wang, Hoau-Yan; Burns, Lindsay H. (2009). "Naloxone's pentapeptide binding site on filamin A blocks Mu opioid receptor-Gs coupling and CREB activation of acute morphine". PLOS ONE. 4 (1): e4282. Bibcode:2009PLoSO...4.4282W. doi:10.1371/journal.pone.0004282. ISSN 1932-6203. PMC 2628740. PMID 19172190.
  35. Burns, Lindsay H.; Wang, Hoau-Yan (2010). "PTI-609: A Novel Analgesic that Binds Filamin A to Control Opioid Signaling". Recent Patents on CNS Drug Discovery. 5 (3): 210–220. doi:10.2174/157488910793362386. PMID 20726836.
  36. Wang, H.-Y.; Bakshi, K.; Frankfurt, M.; Stucky, A.; Goberdhan, M.; Shah, S. M.; Burns, L. H. (2012). "Reducing Amyloid-Related Alzheimer's Disease Pathogenesis by a Small Molecule Targeting Filamin A". Journal of Neuroscience. 32 (29): 9773–9784. doi:10.1523/JNEUROSCI.0354-12.2012. PMC 6621293. PMID 22815492.
  37. Wang, Hoau-Yan; Lee, Kuo-Chieh; Pei, Zhe; Khan, Amber; Bakshi, Kalindi; Burns, Lindsay H. (2017). "PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis". Neurobiology of Aging. 55: 99–114. doi:10.1016/j.neurobiolaging.2017.03.016. PMID 28438486. S2CID 207163555.
  38. Toniolo, Sofia; Sen, Arjune; Husain, Masud (2020). "Modulation of Brain Hyperexcitability: Potential New Therapeutic Approaches in Alzheimer's Disease". International Journal of Molecular Sciences. 21 (23): 9318. doi:10.3390/ijms21239318. PMC 7730926. PMID 33297460.
  39. "Cassava Sciences Announces Lead Drug Candidate PTI-125 Is Assigned the Chemical Drug Name 'sumifilam' by USAN". Global Newswire (Press release). Cassava Sciences. August 24, 2020. Retrieved May 3, 2022.
  40. Piller C (October 12, 2023). Co-developer of Cassava’s potential Alzheimer’s drug cited for ‘egregious misconduct’ (Report). Science. doi:10.1126/science.adl3444.
  41. Subbaraman N, Walker J (October 13, 2023). "Cassava Sciences Adviser Found to Have Committed 'Egregious Misconduct'; Scientist, who is a City University of New York professor, didn't provide school investigators with data or records supporting his research". Wall Street Journal. ProQuest 2876611078.
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