La vraie générosité envers l’avenir consiste à tout donner au présent.

(Real generosity toward the future lies in giving all to the present.)

–Albert Camus

Paul Frenette, MD, an extraordinary physician-scientist, colleague, and friend, died on July 26, 2021, at the age of 56 (Figure 1). Paul was raised in Cap-Santé, Québec, by his father, an elementary school principal, and his mother, a homemaker, along with four siblings. His hometown was a beautiful but sparsely populated village along the St. Lawrence River between Quebec and Montreal. To keep boredom at bay during the summer, Paul and his siblings invented games. The absence of infrastructure was likely fertile ground for the creativity that helped Paul become a great scientist. Although Paul played many sports during his childhood, hockey was far and away his favorite. Paul was a true Philadelphia Flyers fan and appreciated them for their commitment, team spirit, and dedication to the sport. Paul had a keen desire to succeed and the determination to spare no effort to do so in terms of time and energy. No excuse was allowed for not performing at 100%.

Paul S. Frenette, MD. Image credit: Nadine Frenette.

At the age of 15, Paul was diagnosed with stage 4 Hodgkin lymphoma, which caused him to miss many hours of classes and studies due to a plethora of treatments to manage his condition. Nevertheless, he finished first in his class in tenth grade. After all, cancer was not an excuse to finish second! His favorite field for competition had now become school. He graduated among the top in medicine at Université Laval, Quebec City, and in 1985 he was awarded a prestigious summer Terry Fox Scholarship, given to only a very few medical students in Canada. He came to the United States to train as a fellow in hematology-oncology at Tufts Medical Center in 1994. He soon met his future wife, Nadine, at a jazz club in Cambridge, Massachusetts. Paul subsequently received his scientific research training at Massachusetts Institute of Technology and Harvard Medical School. Paul deeply enjoyed studying and working, and he was in his element as a researcher.

Paul began his independent research career in 1998 as Assistant Professor at the Mount Sinai School of Medicine in New York City, where he rose to Professor of Medicine in 2007. He was recruited to the Albert Einstein College of Medicine in 2010 to become the Founding Director and Chair of the Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, where he recruited key faculty members and established it as a premier stem cell research program. He was also Professor of Medicine and Cell Biology.

Paul was an outstanding and very creative scientist who made seminal contributions to several fields of biomedical science, including the stem cell microenvironment in health and cancer and the vascular biology of sickle cell disease. His laboratory broke new ground in sickle cell disease related to vascular occlusion, cell adhesion, thromboinflammation, neutrophil aging, neutrophil extracellular traps, and the microbiome (1–6). Using intravital microscopy, the group discovered that leukocytes play a direct role in vascular occlusion by capturing circulating sickle red blood cells. They went on to show that a wave of neutrophil activation is involved and that E-selectin mediates this activation, suggesting that selectin inhibitors may be beneficial for treating sickle cell vascular occlusion. His research directly enabled clinical trials in sickle cell disease of rivipansel, olinciguat, and IgG. He shared his authoritative vascular pathobiology perspective in a chapter of the textbook Sickle Cell Disease, published just two months before his death.

Paul’s group also made very important contributions to characterizing the bone marrow stem cell niche. They made the paradigm-shifting discovery that the sympathetic nervous system regulates hematopoietic stem cell egress from the niche and described circadian regulation of hematopoietic stem cell migration from the bone marrow (7–12). Paul’s lab identified key stromal constituents of the hematopoietic stem cell niche and demonstrated the important role of macrophages in regulating bone marrow niches. Paul then extended the concept of nervous system control of hematopoietic stem cell migration to understand how cancer cells metastasize by demonstrating that similar signaling exists in prostate cancer models. His lab identified important and distinct functions of the two branches of the autonomic nervous system in prostate cancer progression, showing that the sympathetic nervous system plays a prominent role in cancer initiation, whereas the parasympathetic nervous system (muscarinic receptors) plays a role in spreading of cancer into lymph nodes and distant organs (13, 14).

Paul served on the editorial board of Blood, the board of consulting editors of the Journal of Clinical Investigation, and the Medical Advisory Board of the New York Stem Cell Foundation; as chair of a scientific committee of the American Society of Hematology; and on the Sickle Cell Advisory Council of the National Heart, Lung, and Blood Institute and multiple other panels at the NIH. Paul was elected to the American Society for Clinical Investigation in 2004 and to the Association of American Physicians in 2010.

Paul’s work was gigantic: always a topic of importance, always interesting at the level in basic biology, yet always with a clear connection to medicine. Paul considered himself a doctor first and then a researcher, and his physician training guided him in the topics he studied. It also made him flexible and creative in his approach. The discovery of neural circadian circuits regulating the bone marrow niche came about because of a lighting miscue in the animal facility. It was a mistake, but Paul could see in it a discovery that changed many people’s perception of a niche and its connection to complex organism-level physiology. He delighted in a quirky, odd moment leading to a fundamental insight. That joy carried over to how he cared for his mentees and colleagues. There were no moments with Paul that went without his broad, warm smile, lilting laugh, and often a twist of irony. He conducted even disagreement with a light, kind touch and did service to the field without fanfare or ego. His contributions will forever carry his distinct signature of joie de vivre.

In science, Paul was the Happy Warrior, generous in spirit, virtuously coveting truth, and competing every day to attract the best students and to fund, publish, and share his work. His talent, coupled with his endless determination, elevated him to among the best in his field. The Latin maxim that he often heard from his father during childhood was “excelsior,” which means always higher, always further, and this ethos continued to resonate throughout Paul’s life.

Paul was a devoted father to his children, Clara and Albéric. An amateur enologist, he enjoyed visiting wineries and vineyards and meeting vintners. He also had a passion for music, and he and Nadine often went to concerts by the New York Philharmonic. Paul will be deeply missed by his friends, colleagues, and family. His legacy will live on through his discoveries and students, and his exemplary life of living and working to the fullest.

Acknowledgments

We thank Nadine Frenette, Jérôme Frenette, David Scadden, Greg Kato, and Mark Gladwin for sharing their memories and insights.

Footnotes

Copyright: © 2021, American Society for Clinical Investigation.

Reference information: J Clin Invest. 2021;131(20):e155100. https://doi.org/10.1172/JCI155100.

References

1. Xu C, et al. Nociceptors protect sickle cell disease mice from vaso-occlusive episodes and chronic organ damage. J Exp Med. 2021;218(1):e20200065. View this article via: PubMedCrossRefGoogle Scholar
2. Manwani D, et al. Randomized phase 2 trial of intravenous gamma globulin (IVIG) for the treatment of acute vaso-occlusive crisis in patients with sickle cell disease: lessons learned from the midpoint analysis. Complement Ther Med. 2020;52:102481. View this article via: PubMedGoogle Scholar
3. Zhang D, et al. Neutrophil ageing is regulated by the microbiome. Nature. 2015;525(7570):528–532.View this article via: PubMedCrossRefGoogle Scholar
4. Jang JE, et al. CXCL1 and its receptor, CXCR2, mediate murine sickle cell vaso-occlusion during hemolytic transfusion reactions. J Clin Invest. 2011;121(4):1397–1401.View this article via: JCIPubMedCrossRefGoogle Scholar
5. Hidalgo A, et al. Heterotypic interactions enabled by polarized neutrophil microdomains mediate thromboinflammatory injury. Nat Med. 2009;15(4):384–391.View this article via: PubMedCrossRefGoogle Scholar
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8. Gao X, et al. Nociceptive nerves regulate haematopoietic stem cell mobilization. Nature. 2021;589(7843):591–596.View this article via: PubMedCrossRefGoogle Scholar
9. Wei Q, et al. Snai2 maintains bone marrow niche cells by repressing osteopontin expression. Dev Cell. 2020;53(5):503–513.View this article via: PubMedCrossRefGoogle Scholar
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La vraie générosité envers l'avenir combinee à tout donner au présent。

（对未来真正的慷慨在于把一切都奉献给现在。）

——阿尔伯特·加缪

医学博士 Paul Frenette 是一位杰出的内科医生、科学家、同事和朋友，于 2021 年 7 月 26 日去世，享年 56 岁（图 1）。保罗在魁北克的 Cap-Santé 长大，他的父亲是一名小学校长，他的母亲是一名家庭主妇，还有四个兄弟姐妹。他的家乡是魁北克和蒙特利尔之间圣劳伦斯河沿岸的一个美丽但人口稀少的村庄。为了避免在夏天感到无聊，保罗和他的兄弟姐妹发明了游戏。基础设施的缺乏可能为帮助保罗成为伟大科学家的创造力提供了沃土。尽管保罗在童年时期参加了许多运动，但曲棍球却是他的最爱。保罗是费城飞人队的忠实粉丝，感谢他们对这项运动的承诺、团队精神和奉献精神。保罗对成功有着强烈的渴望，并决心在时间和精力上不遗余力地做到这一点。没有任何借口不能 100% 执行。

Paul S. Frenette，医学博士。图片来源：Nadine Frenette。

在 15 岁时，保罗被诊断出患有 4 期霍奇金淋巴瘤，这导致他因大量治疗来控制病情而缺席了许多小时的课程和学习。尽管如此，他还是在十年级时以全班第一名的成绩取得了成绩。毕竟，癌症不是获得第二名的借口！他最喜欢的比赛场地现在变成了学校。他毕业于魁北克市拉瓦尔大学的医学专业名列前茅，并于 1985 年获得了享有盛誉的夏季特里福克斯奖学金，该奖学金仅授予加拿大极少数医学生。1994 年，他来到美国，在塔夫茨医学中心接受血液肿瘤学培训。很快，他在马萨诸塞州剑桥市的一家爵士乐俱乐部遇到了未来的妻子纳丁。保罗随后在麻省理工学院和哈佛医学院接受了科学研究培训。保罗非常喜欢学习和工作，他是一名研究人员。

保罗于 1998 年开始他的独立研究生涯，担任纽约市西奈山医学院的助理教授，并于 2007 年晋升为医学教授。他于 2010 年被阿尔伯特爱因斯坦医学院聘为创始董事Ruth L. 和 David S. Gottesman 干细胞和再生医学研究所主席，在那里他招募了主要教员，并将其建立为首要的干细胞研究项目。他还是医学和细胞生物学教授。

保罗是一位杰出且极具创造力的科学家，他对生物医学科学的多个领域做出了开创性贡献，包括健康和癌症中的干细胞微环境以及镰状细胞病的血管生物学。他的实验室在与血管闭塞、细胞粘附、血栓炎症、中性粒细胞老化、中性粒细胞胞外陷阱和微生物组相关的镰状细胞病方面开辟了新天地 ( 1 –6）。使用活体显微镜，该小组发现白细胞通过捕获循环镰状红细胞在血管闭塞中发挥直接作用。他们继续表明涉及一波中性粒细胞活化，并且 E-选择素介导这种活化，表明选择素抑制剂可能有益于治疗镰状细胞血管闭塞。他的研究直接促成了 rivipansel、olinciguat 和 IgG 镰状细胞病的临床试验。在他去世前两个月出版的教科书镰状细胞病的一章中，他分享了他权威的血管病理学观点。

保罗的小组也为表征骨髓干细胞生态位做出了非常重要的贡献。他们做出了范式转换的发现，即交感神经系统调节造血干细胞从生态位的流出，并描述了造血干细胞从骨髓迁移的昼夜节律调节 ( 7 –12 )。Paul 的实验室确定了造血干细胞生态位的关键基质成分，并证明了巨噬细胞在调节骨髓生态位中的重要作用。保罗随后扩展了造血干细胞迁移的神经系统控制的概念，通过证明前列腺癌模型中存在类似的信号传导来了解癌细胞如何转移。他的实验室确定了自主神经系统两个分支在前列腺癌进展中的重要而不同的功能，表明交感神经系统在癌症的发生中起着重要作用，而副交感神经系统（毒蕈碱受体）在前列腺癌的扩散中起着重要作用。癌细胞转移到淋巴结和远处器官（13、14 )。

Paul 曾在Blood编辑委员会、Journal of Clinical Investigation咨询编辑委员会和纽约干细胞基金会医学顾问委员会任职；担任美国血液学会科学委员会主席；以及国家心肺血液研究所镰状细胞咨询委员会和 NIH 的多个其他小组。Paul was elected to the American Society for Clinical Investigation in 2004 and to the Association of American Physicians in 2010.

保罗的工作是巨大的：总是一个重要的话题，在基础生物学层面总是很有趣，但总是与医学有明确的联系。保罗首先认为自己是一名医生，然后是一名研究人员，他所接受的医师培训指导了他研究的主题。这也使他的方法灵活而富有创造力。调节骨髓生态位的神经昼夜节律回路的发现源于动物设施中的照明错误。这是一个错误，但保罗可以从中看出一个发现，它改变了许多人对生态位及其与复杂生物体水平生理学的联系的看法。他对一个古怪的、奇怪的时刻感到高兴，从而获得了基本的洞察力。这种喜悦延续到他如何照顾他的学员和同事。与保罗在一起的每一刻都离不开他宽阔而温暖的微笑，轻快的笑声，常常带有讽刺意味。他甚至以轻松、善意的方式处理分歧，并在没有大张旗鼓或自负的情况下为该领域服务。他的贡献将永远带有他独特的生活乐趣标志。

在科学领域，保罗是个快乐的战士，精神大方，渴望真理，每天都在竞相吸引最优秀的学生，资助、出版和分享他的工作。他的才华，加上他无尽的决心，使他成为了他所在领域的佼佼者。童年时他经常从父亲那里听到的拉丁格言是“excelsior”，意思是永远更高，永远更远，这种精神在保罗的一生中继续产生共鸣。

保罗是他的孩子克拉拉和阿尔贝里克的忠实父亲。作为一名业余酿酒师，他喜欢参观酿酒厂和葡萄园并会见葡萄酒商。他也对音乐充满热情，他和 Nadine 经常去纽约爱乐乐团的音乐会。他的朋友、同事和家人将深深怀念保罗。他的遗产将通过他的发现和学生，以及他过着充实的生活和工作的模范生活而继续存在。

致谢

我们感谢 Nadine Frenette、Jérôme Frenette、David Scadden、Greg Kato 和 Mark Gladwin 分享他们的回忆和见解。

脚注

版权所有： © 2021，美国临床调查协会。

参考资料：J Clin Invest。2021;131(20):e155100。https://doi.org/10.1172/JCI155100。

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