Lindsay Burns Explained

Lindsay Burns
Birth Place:Big Timber, Montana, U.S.
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Lindsay H. Burns (born 1965) is an American neuroscientist and rower who won a silver medal at the 1996 Summer Olympics.[1] She was a senior vice president of the pharmaceutical company Cassava Sciences[2] until July 2024 and married to its CEO Remi Barbier.

As of July 2022, Cassava Sciences and papers co-authored by Burns were under investigation;[3] [4] co-author Hoau-Yan Wang was indicted for fraud in 2024 and Cassava denies any wrongdoing. Burns and her husband, Remi Barbier (president and chief executive officer of Cassava)[5] [6] abruptly resigned in 2024 following Wang's indictment.[7] [8]

Personal life

Burns was born in 1965[9] and raised in Big Timber, Montana. She graduated from Harvard University in 1987. In 1991, she obtained a PhD in neuroscience from University of Cambridge 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.[13] She joined Cassava Sciences in 2002 and became senior vice president of neuroscience in 2021.[14]

Burns is married to Remi Barbier, the former CEO[7] [8] and founder of Cassava Sciences.[15] [16]

Rowing career

Burns started competitive rowing soon after entering Harvard.[13] 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. She was part of the US rowing team from 1987 and from 1990 to 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 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. In 2006, she was inducted into the Harvard Sports Hall of Fame.[18] In 2016, she was inducted into the National Rowing Foundation Hall of Fame.[19]

Scientific works

Burns's 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.[20] She continued her PhD research on the role of dopamine and the limbic system.[21] [22] 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.[23] Further research indicated possible use in humans.[24] 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.[25]

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.[26] [27] [28]

Since 2006, Burns collaborated with Hoau-Yan Wang at the City University of New York,[29] who had been investigating Alzheimer's disease. Burns and Wang wrote that FLNA was a critical protein in enabling Abeta42's signaling through the alpha 7 nicotinic acetylcholine receptor to induce Alzheimer's disease pathology (the publication has an expression of concern).[30] [31] [32]

FLNA, simufilam and Alzheimer's disease

In 2008, Burns, Wang and Maya Frankfurt published in PLOS One a (later retracted) 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 published (now retracted) 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 (now with an expression of concern) a novel compound PTI-125 that binds to FLNA similarly to naloxone and naltrexone. 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 stated in Neurobiology of Aging (now with an expression of concern) 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

In June 2024, Wang was indicted by the United States Department of Justice (DOJ) for fraud and charged with falsifying data on $16 million in grant applications to the NIH related to the Alzheimer's drug in development, simufilam.[40] [41] [42] [43] As of July 2022, Cassava Sciences and papers published by Burns and Wang were under investigation by the DOJ; Cassava denies any wrongdoing.[44] [45] [46] 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.[46]

In October 2023, CUNY reported that they could obtain none of Wang's original data.[47] [48] According to The Wall Street Journal, the CUNY report stated that Burns shared with Wang some responsibility "for errors and misconduct".[48]

External links

Notes and References

  1. Web site: Biography: Lindsay Burns . 2022-05-02 . Olympics . International Olympic Committee.
  2. Web site: Keown . Alex . 2022-04-19 . Cassava Faces Renewed Speculation Over Experimental Alzheimer's Drug . 2022-05-09 . BioSpace . en-US.
  3. News: Mandavilli . Apoorva . 2022-04-18 . Scientists Question Data Behind an Experimental Alzheimer's Drug . The New York Times . 2022-04-28 . 0362-4331.
  4. Web site: The Cassava Sciences saga: Short sellers, 'gaming' the FDA, and the damaging ripple effects.
  5. Web site: Management . Cassava Sciences . July 18, 2024 . https://web.archive.org/web/20240628190423/https://www.cassavasciences.com/management . June 28, 2024.
  6. Web site: Feuerstein . Adam . April 5, 2022 . Troubles mount for Cassava Sciences, as patient enrollment lags for Alzheimer's drug studies . April 30, 2022 . Stat.
  7. News: With resignations of top leaders, Cassava Sciences exposes a dark, ugly corner of the Alzheimer's disease world . STAT news . July 17, 2024 . July 18, 2024 . Adam . Feuerstein.
  8. Cassava Sciences Announces Changes in Executive Leadership, Enhanced Corporate Governance and Other Initiatives. Cassava Sciences . July 17, 2024 . July 18, 2024 .
  9. Web site: Lindsay Burns. World Rowing.
  10. Functional interactions of limbic afferents to the striatum and mesolimbic dopamine in reward-related processes . University of Cambridge . 1991 . Ph.D. . Lindsay H. . Burns . 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 . en . 55 . 2 . 167–183 . 10.1016/0166-4328(93)90113-5 . 8357526 . 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 . en . 115 . 4 . 516–528 . 10.1007/BF02245576 . 7871097 . 28351013.
  13. Web site: Harvard at the Olympics . 2022-05-03 . Harvard Magazine.
  14. Web site: Lindsay H Burns, Cassava Sciences Inc: Profile and Biography . 2022-05-03 . Bloomberg.com . en.
  15. Keefe . Patrick Radden . January 15, 2022 . Jordan Thomas's Army of Whistle-Blowers . April 29, 2022 . . https://web.archive.org/web/20220722085539/https://www.newyorker.com/magazine/2022/01/24/jordan-thomas-army-of-whistle-blowers . July 22, 2022 . live . limited.
  16. Web site: Feuerstein . Adam . 2022-04-05 . Troubles mount for Cassava Sciences, as patient enrollment lags for Alzheimer's drug studies . 2022-04-30 . STAT . en-US.
  17. Web site: Rowing News . 16–29 July 1995 .
  18. Web site: Lindsay Burns Barbier '87 . 2022-05-02 . www.harvardvarsityclub.org . en . June 2, 2022 . https://web.archive.org/web/20220602060442/https://www.harvardvarsityclub.org/article.html?aid=532 . dead .
  19. Web site: The National Rowing Foundation Announces the 2016 Inductees to the National Rowing Hall of Fame . January 26, 2016 .
  20. 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 . en . 31 . 2 . 255–263 . 10.1016/0091-3057(88)90343-7. 2469085 . 20941335 .
  21. 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 . en . 110 . 1 . 60–73 . 10.1037/0735-7044.110.1.60 . 8652073 . 1939-0084.
  22. 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 . en . 19 . 6 . 2401–2411 . 10.1523/JNEUROSCI.19-06-02401.1999 . 6782569 . 10066290.
  23. 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 . en . 1 . 11 . 1189–1194 . 10.1038/nm1195-1189. 7584993 . 7344970 .
  24. 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 . en . 140 . 1 . 1–13 . 10.1006/exnr.1996.0109. 8682173 . 23945411 . free .
  25. 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 . en . 30 . 2 . 334–343 . 10.1016/S0741-5214(99)70145-X. 10436454 . free .
  26. 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 . en . 6 . 6 . 392–399 . 10.1016/j.jpain.2005.01.356. 15943961 . free .
  27. 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 . en . 181 . 3 . 576–581 . 10.1007/s00213-005-0022-7. 16010543 . 13270740 .
  28. 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 . en . 82 . 2 . 252–262 . 10.1016/j.pbb.2005.08.008. 16182352 . 25513761 .
  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 . en . 66 . 12 . 1302–1310 . 10.1002/neu.20286. 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 . 10.1523/JNEUROSCI.0354-12.2012 . 22815492 . 6621293 . 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 . 10.20517/2347-8659.2017.50 . 8294116 . 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 . en . 17 . S5 . online . 10.1002/alz.054385. 245570217 .
  33. Wang . Hoau-Yan . Frankfurt . Maya . Burns . Lindsay H. . 2008-02-06 . High-affinity naloxone binding to filamin a prevents mu opioid receptor-Gs coupling underlying opioid tolerance and dependence . PLOS ONE . 3 . 2 . e1554 . 10.1371/journal.pone.0001554 . 2212716 . 18253501. 2008PLoSO...3.1554W . free .
  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 . 10.1371/journal.pone.0004282 . 1932-6203 . 2628740 . 19172190. 2009PLoSO...4.4282W . free .
  35. Burns . Lindsay H. . Wang . Hoau-Yan . PTI-609: A Novel Analgesic that Binds Filamin A to Control Opioid Signaling . Recent Patents on CNS Drug Discovery . 2010 . en . 5 . 3 . 210–220 . 10.2174/157488910793362386 . 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 . en . 32 . 29 . 9773–9784 . 10.1523/JNEUROSCI.0354-12.2012 . 6621293 . 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 . en . 55 . 99–114 . 10.1016/j.neurobiolaging.2017.03.016. 28438486 . 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 . 10.3390/ijms21239318 . 7730926 . 33297460. free .
  39. Cassava Sciences . Global Newswire. 2020-08-24 . Cassava Sciences Announces Lead Drug Candidate PTI-125 Is Assigned the Chemical Drug Name 'sumifilam' by USAN . 2022-05-03.
  40. Cassava Sciences Issues Statement on Former Science Advisor . Cassava Sciences . June 28, 2024 . June 29, 2024.
  41. News: Embattled Alzheimer's Researcher Is Charged With Fraud . The New York Times . June 28, 2024 . Apoorva . Mandavilli . 29 June 2024.
  42. News: Cassava Sciences collaborator charged with defrauding NIH in grants supporting its Alzheimer's drug . Stat News . Jonathan . Wosen . June 28, 2024 . June 29, 2024.
  43. News: Cassava Sciences Adviser Indicted on Fraud Charges . The Wall Street Journal . June 28, 2024 . June 29, 2024 . Joseph . Walker.
  44. News: Taylor . Marisa . Spector . Mike . July 27, 2022 . Exclusive: Cassava Sciences faces U.S. criminal probe tied to Alzheimer's drug, sources say . Reuters . July 31, 2022.
  45. Cassava Sciences Responds to Media Reports . July 27, 2022 . Cassava Sciences . August 16, 2022.
  46. News: Michaels . Dave . Walker . Joseph . November 17, 2021 . SEC Investigating Cassava Sciences, Developer of Experimental Alzheimer's Drug . en-US . Wall Street Journal . April 29, 2022 . 0099-9660.
  47. Co-developer of Cassava's potential Alzheimer's drug cited for 'egregious misconduct' . Piller C . October 12, 2023 . Science . 10.1126/science.adl3444 . Charles Piller.
  48. News: 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 . Subbaraman N, Walker J. Wall Street Journal . 13 October 2023 . .

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