Michael F. Holick
Michael F. Holick | |
---|---|
Born | 1946 (age 77–78) |
Citizenship | American |
Alma mater | University of Wisconsin–Madison |
Known for | Vitamin D research |
Scientific career | |
Institutions | Boston University Medical Center |
Michael F. Holick (/ˈhɒlɪk/ HOLL-ik;[1] born 1946) is an American adult endocrinologist, specializing in vitamin D, such as the identification of both calcidiol, the major circulating form of vitamin D, and calcitriol, the active form of vitamin D. His work has been the basis for diagnostic tests and therapies for vitamin D-related diseases. He is a professor of medicine at the Boston University Medical Center and editor-in-chief of the journal Clinical Laboratory.
Professional activities
[edit]After earning a Ph.D. degree in biochemistry, a medical degree, and completing a research postdoctoral fellowship at the University of Wisconsin–Madison, Holick completed a residency in medicine at the Massachusetts General Hospital in Boston.[2]
He is an adult endocrinologist and professor of medicine, physiology and biophysics and director of the Bone Health Care Clinic and the Heliotherapy, Light, and Skin Research Center at Boston University Medical Center.[3] It provides extensive evaluation and treatment programs for children and adults with various metabolic bone diseases including osteoporosis, osteomalacia, stress fractures in young athletic women and men, and minimum trauma and nontraumatic fractures in infants, children and adults with hypermobility syndromes, Osteogenesis imperfecta, and Ehlers Danlos Syndrome.[4] He has been director of the General Clinical Research Unit at Boston University for several years.[2]
Holick serves as chair of NASA's "Human Health Countermeasures Element" Standing Review Panel,[5] chair of the Endocrine Practice Guidelines Committee for Vitamin D,[6] and editor-in-chief of the medical journal Clinical Laboratory.[7]
Academic achievements and research
[edit]Holick made discoveries in the field of vitamin D that have led to novel therapies for metabolic bone diseases, hypocalcemic disorders, and psoriasis. He is author of more than 400 publications about the biochemistry, physiology, metabolism and photobiology of vitamin D and the pathophysiology of vitamin D deficiency.[8]
His scientific work increased awareness in the pediatric and medical communities regarding vitamin D deficiency,[9] and its role in causing not only metabolic bone disease, and osteoporosis in adults, but increasing risk of children and adults developing common deadly cancers, autoimmune diseases, including type 1 diabetes, multiple sclerosis and heart disease,[10] as discussed in his review article.[10]
He has been quoted and his scientific work has been referenced in The New York Times,[11] Forbes,[12][13] Newsweek,[14] Men's Health,[15] Scientific American[16] and Time.[17] He wrote several books about the importance of vitamin D and its beneficial health effects to the broad public, and discussed the benefits of sensible and the risks of excessive sun exposure.[18][19]
As a graduate student, he identified the major circulating form of vitamin D, 25-hydroxyvitamin D3,[20] which is the vitamin D metabolite that is measured by physicians worldwide to determine a patient's vitamin D status.[21] He also identified the active form of vitamin D, 1,25-dihydroxyvitamin D3,[22] as well as other metabolites including 24,25-dihydroxyvitamin D3,[23] 1,24,25-trihydroxyvitamin D3[24] and 25,26-dihydroxyvitamin D3.[25]
As a fellow, he participated in the first chemical synthesis of 1,25-dihydroxyvitamin D3[26] and 1α-hydroxyvitamin D3[27] to treat renal osteodystrophy,[28] hypoparathyroidism,[29][30] vitamin D dependent rickets type I,[31] and osteoporosis.[32] Furthermore, he elucidated the pathophysiology of hereditary vitamin D-dependent rickets which involves defective vitamin D metabolism,[33] and the pathophysiological mechanisms of X-linked hypophosphatemic rickets.[34]
Holick helped develop the first clinical assays for 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D,[35] determined how vitamin D3 is made in the skin from sun exposure,[36] and established how season,[37] time of day,[38] skin pigmentation,[39] sunscreen use,[40] and latitude[37] influenced this vital cutaneous process. He established that the skin was not only the organ responsible for making vitamin D3[36] but was also a target tissue for its active form, 1,25-dihydroxyvitamin D3.[41] He determined the extremely inhibitory effects of 1,25-dihydroxyvitamin D3 on keratinocyte proliferation and the promoting effects on differentiation,[41] and translated these seminal observations by demonstrating that the topical application of 1,25-dihydroxyvitamin D3 and several of its analogs were effective for the treatment of psoriasis.[42]
He demonstrated that macrophages[43] and prostate cells[44] have the enzymatic machinery to produce 1,25-dihydroxyvitamin D3, and established that the extrarenal production of 1,25-dihydroxyvitamin D3 may play a crucial role not only in cancer prevention but also in regulating the immune system.[45]
He developed a vitamin D absorption test[46] and demonstrated that vitamin D was bioavailable in orange juice, leading to fortification of juice products in the United States.[47] He also used the test to demonstrate the major cause of vitamin D deficiency in obesity is sequestration of vitamin D in the fat.[48]
He helped perform dose escalation studies establishing how much vitamin D is required to maintain blood levels of 25-hydroxyvitamin D in the sufficient range for adults. These studies also demonstrated that up to 10,000 IU of vitamin D a day for 5 months did not cause toxicity.[49]
Controversies
[edit]Holick has been involved in several medical controversies. While at Boston University, he was asked to leave the Division of Dermatology because of his promoting the medical benefits of sun exposure. He accepted research funding for this work from a non-profit tanning bed company, considered by many to be an important potential bias. Barbara Gilchrest, then head of the department at Boston University, called Holick's book "shlock science" and Holick "a poster boy for the tanning industry".[50]
Holick received nearly $163,000 from 2013 to 2017 from pharmaceutical companies, according to Medicare’s Open Payments database, which tracks payments from drug and device manufacturers. The companies paying him included Sanofi-Aventis, which markets vitamin D supplements; Shire, which makes drugs for hormonal disorders that are given with vitamin D; Amgen, which makes an osteoporosis treatment; and Roche Diagnostics and Quidel Corp., which both make vitamin D tests.[51]
Holick has also been criticized by other physicians because of his testimony, defending accused child abusers by asserting that Ehlers–Danlos syndrome is a cause of non-traumatic fractures in infancy (rather than abuse).[52] In one case of a child who had suffered broken bones in which Holick defended the accused parent, the child later went on to suffer severe brain injury, for which the parent, named Robert Marvin Ray, has been indicted.[50][53][54][55]
Since May 2017, Holick has been barred from evaluating or treating children by Boston Medical Center, which subsequently reported him to the Massachusetts Board of Registration in Medicine for "health care facility discipline",[54] but is still allowed to evaluate children who are participating in his research project.[55] Boston University has defended Holick's right to testify in courts, as part of his academic freedom.[55]
Holick has speculated that the dinosaurs may have died of rickets and osteomalacia caused by a lack of vitamin D in reduced sunlight.[56]
A paper on Vitamin D to treat COVID19 has been retracted.[57]
Awards
[edit]Holick has been awarded for his contributions to the field of vitamin D research with prizes,[58] including:
- Merit Award from the National Institute of Health
- American Society for Bone and Mineral Research Fuller Albright Award
- Mead Johnson Award
- Osborne and Mendel Award, the McCollum Award
- Robert H. Herman Award from the American Society for Clinical Nutrition
- ACN Award from the American College of Nutrition
- NIH’s General Clinical Research Center's Program Award for Excellence in Clinical Research
- Psoriasis Research Achievement Award from the American Skin Association[2]
- DSM Innovation in Nutrition Award[59]
- Van Slyke Award from American Association for Clinical Chemistry[60]
- Linus Pauling Prize In Human Nutrition[61]
- Delbert A Fisher Research Scholar Award from the Endocrine Society[62]
- American College of Nutrition's Communication Media Award[63]
- Institute of Functional Medicine’s LPI Award 2007[64]
Selected publications
[edit]Books
[edit]- Holick, MF (2011). The Vitamin D Solution: A 3-Step Strategy to Cure Our Most Common Health Problems. Plume 1st edition. ISBN 978-0452296886.
- Holick, MF; Dawson-Hughes, B (2010) [2004]. Nutrition and Bone Health. Humana Press. ISBN 978-1617374517.
- Holick, MF, ed. (2010). Vitamin D: Physiology, Molecular Biology, and Clinical Applications (2nd ed.). Humana Press. ISBN 978-1603273008.
- Holick, MF; Jenkins, Mark (2005). UV Advantage (2nd ed.). IBOOKS. ISBN 978-1596879003.
Scientific journal articles
[edit]- Holick, MF (2007). "Vitamin D deficiency". N Engl J Med. 357 (3): 266–81. doi:10.1056/NEJMra070553. PMID 17634462. S2CID 18566028.
- Holick, MF (2006). "Resurrection of vitamin D deficiency and rickets". J Clin Invest. 116 (8): 2062–72. doi:10.1172/JCI29449. PMC 1523417. PMID 16886050.
- Pietras, SM; Obayan, BK; Chai, MH; Holick, MF (2010). "Vitamin D2 treatment for vitamin D deficiency and insufficiency for up to 6 years". Arch Intern Med. 169 (19): 1806–8. doi:10.1001/archinternmed.2009.361. PMID 19858440.
- Biancuzzo, RM; Young, A; Bibuld, D; Cai, MH; Winter, RM; Klein, EK; Ameri, A; Reitz, R; Salameh, W; Chen, TC; Holick, MF (2010). "Fortification of orange juice with vitamin D(2) or vitamin D(3) is as effective as an oral supplement in maintaining vitamin D status in adults". Am J Clin Nutr. 91 (6): 1621–6. doi:10.3945/ajcn.2009.27972. PMC 2869510. PMID 20427729.
- Holick, MF; Binkley, NC; Bischoff-Ferrari, HA; Gordon, CM; Hanley, DA; Heaney, RP; Murad, MH; Weaver, CM; et al. (2011). "Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline". J Clin Endocrinol Metab. 96 (7): 1911–30. doi:10.1210/jc.2011-0385. PMID 21646368.
References
[edit]- ^ "Michael F Holick- Vitamin D Deficiency and Possible Role in Multiple Sclerosis". YouTube. 3 March 2016. Retrieved 23 May 2020.
- ^ a b c "med.harvard.edu - Biographical Sketch M.F. Holick" (PDF). Archived from the original (PDF) on 2010-06-27.
- ^ "Boston University School of Medicine, Michael F. Holick Ph.D., M.D." Archived from the original on 2012-06-10.
- ^ "Vitamin D and Bone Metabolism Unit at Boston University".
- ^ "Human Research Program 2010 Chair Standing Review Panel Meeting" (PDF).
- ^ Holick, MF; Binkley, NC; Bischoff-Ferrari, HA; Gordon, CM; Hanley, DA; Heaney, RP; Murad, MH; Weaver, CM; et al. (2011). "Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline". J Clin Endocrinol Metab. 96 (7): 1911–30. doi:10.1210/jc.2011-0385. PMID 21646368.
- ^ "Journal of Clinical Laboratory - Editorial Board - Editor-In-Chief - MF Holick". Archived from the original on 2013-01-19.
- ^ "Harvard Catalyst Profiles: Michael Holick".
- ^ Holick, MF; Chen, TC (2008). "Vitamin D deficiency: a worldwide problem with health consequences". Am J Clin Nutr. 87 (4): 1080S–6S. doi:10.1093/ajcn/87.4.1080s. PMID 18400738.
- ^ a b Holick, MF (2007). "Vitamin D deficiency". N Engl J Med. 357 (3): 266–81. doi:10.1056/NEJMra070553. PMID 17634462. S2CID 18566028.
- ^ Solomon, Interview by Deborah (19 March 2010). "Dr. Sunshine". The New York Times.
- ^ "Update on Fibromyalgia and Vitamin D". Forbes.
- ^ "Why You Should Be Getting More Sun". Forbes.
- ^ "The nature of nutrients". The Daily Beast. Archived from the original on 2012-01-25. Retrieved 2012-06-06.
- ^ "Get some sun". Archived from the original on 2013-11-05.
- ^ "Scientific American - The Vitamin D and sun debate". Scientific American.
- ^ "Bibliography M.F. Holick". Amazon.
- ^ "Books - Michael F. Holick". Amazon.
- ^ Holick, MF (2011). The Vitamin D Solution: A 3-Step Strategy to Cure Our Most Common Health Problems. Plume 1st edition. ISBN 978-0452296886.
- ^ Holick, MF; Deluca, HF; Avioli, LV (1972). "Isolation and identification of 25-hydroxycholecalciferol from human plasma". Archives of Internal Medicine. 129 (1): 56–61. doi:10.1001/archinte.1972.00320010060005. PMID 4332591.
- ^ Hollis, BW (1996). "Assessment of vitamin D nutritional and hormonal status: what to measure and how to do it". Calcif Tissue Int. 58 (1): 4–5. doi:10.1007/BF02509538. PMID 8825231. S2CID 35887181.
- ^ Holick, MF; Schnoes, HK; Deluca, HF; Suda, T; Cousins, RJ (1971). "Isolation and identification of 1,25-dihydroxycholecalciferol. A metabolite of vitamin D active in intestine". Biochemistry. 10 (14): 2799–804. doi:10.1021/bi00790a023. PMID 4326883.
- ^ Holick, MF; Schnoes, HK; Deluca, HF; Gray, RW; Boyle, IT; Suda, T (1972). "Isolation and identification of 24,25-dihydroxycholecalciferol, a metabolite of vitamin D made in the kidney". Biochemistry. 11 (23): 4251–5. doi:10.1021/bi00773a009. PMID 4342902.
- ^ Holick, MF; Kleiner-Bossaller, A; Schnoes, HK; Kasten, PM; Boyle, IT; Deluca, HF (1973). "1,24,25-Trihydroxyvitamin D3. A metabolite of vitamin D3 effective on intestine". The Journal of Biological Chemistry. 248 (19): 6691–6. doi:10.1016/S0021-9258(19)43408-X. PMID 4355503.
- ^ Deluca, HF; Suda, T; Schnoes, HK; Tanaka, Y; Holick, MF (1970). "25,26-dihydroxycholecalciferol, a metabolite of vitamin D3 with intestinal calcium transport activity". Biochemistry. 9 (24): 4776–80. doi:10.1021/bi00826a022. PMID 4319987.
- ^ Holick, MF; Schnoes, HK; DeLuca, HF (April 1971). "Identification of 1,25-dihydroxycholecalciferol, a form of vitamin D3 metabolically active in the intestine". Proc. Natl. Acad. Sci. U.S.A. 68 (4): 803–4. Bibcode:1971PNAS...68..803H. doi:10.1073/pnas.68.4.803. PMC 389047. PMID 4323790.
- ^ Holick, M.; Holick, S.; Tavela, T; Gallagher, B; Schnoes, H.; Deluca, H. (1975). "Synthesis of (6-3H)-1alpha-hydroxyvitamin D3 and its metabolism in vivo to (3H)-1alpha,25-dihydroxyvitamin D3". Science. 190 (4214): 576–8. doi:10.1126/science.1188356. PMID 1188356. S2CID 21530294.
- ^ Silverberg, DS; Bettcher, KB; Dossetor, JB; Overton, TR; Holick, MF; Deluca, HF (1975). "Effect of I,25-dihydroxycholecalciferol in renal osteodystrophy". Canadian Medical Association Journal. 112 (2): 190, 193–5. PMC 1956416. PMID 1111876.
- ^ Kooh, Sang Whay; Fraser, Donald; Deluca, Hector F.; Holick, Michael F.; Belsey, Richard E.; Clark, Mary B.; Murray, Timothy M. (1975). "Treatment of Hypoparathyroidism and Pseudohypoparathyroidism with Metabolites of Vitamin D: Evidence for Impaired Conversion of 25-Hydroxyvitamin D to 1α,25-Dihydroxyvitamin D". New England Journal of Medicine. 293 (17): 840–4. doi:10.1056/NEJM197510232931702. PMID 170516.
- ^ Neer, R.M.; Holick, M.F.; Deluca, H.F.; Potts, J.T. (1975). "Effects of 1α-hydroxy-vitamin D3 and 1,25-dihydroxy-vitamin D3 on calcium and phosphorus metabolism in hypoparathyroidism". Metabolism. 24 (12): 1403–13. doi:10.1016/0026-0495(75)90055-4. PMID 1196134.
- ^ Balsan, S; Garabedian, M; Sorgniard, R; Holick, MF; Deluca, HF (1975). "1,25-dihydroxyvitamin D3 and 1, alpha-hydroxyvitamin D3 in children: Biologic and therapeutic effects in nutritional rickets and different types of vitamin D resistance". Pediatric Research. 9 (7): 586–93. doi:10.1203/00006450-197507000-00007. PMID 169507.
- ^ Holick, MF (2007). "Optimal vitamin D status for the prevention and treatment of osteoporosis". Drugs & Aging. 24 (12): 1017–29. doi:10.2165/00002512-200724120-00005. PMID 18020534. S2CID 36958840.
- ^ Fraser, Donald; Kooh, Sang Whay; Kind, H. Peter; Holick, Michael F.; Tanaka, Yoko; Deluca, Hector F. (1973). "Pathogenesis of Hereditary Vitamin-D-Dependent Rickets". New England Journal of Medicine. 289 (16): 817–22. doi:10.1056/NEJM197310182891601. PMID 4357855.
- ^ Glorieux, FH; Holick, MF; Scriver, CR; Deluca, HF (1973). "X-linked hypophosphataemic rickets: Inadequate therapeutic response to 1,25-dihydroxycholecalciferol". Lancet. 2 (7824): 287–9. doi:10.1016/s0140-6736(73)90793-9. PMID 4124774.
- ^ Clemens, TL; Adams, JS; Nolan, JM; Holick, MF (1982). "Measurement of circulating vitamin D in man". Clinica Chimica Acta. 121 (3): 301–8. doi:10.1016/0009-8981(82)90239-X. PMID 6286167.
- ^ a b Holick, MF; MacLaughlin, JA; Clark, MB; Holick, SA; Potts, JT junior; Anderson, RR; Blank, IH; Parrish, JA; et al. (1980). "Photosynthesis of previtamin D3 in human skin and the physiologic consequences". Science. 210 (4466): 203–205. Bibcode:1980Sci...210..203H. doi:10.1126/science.6251551. PMID 6251551.
- ^ a b Webb, AR; Kline, L; Holick, MF; Nielsen, CT; Price, PA; Christiansen, C; Skakkebaek, NE (1988). "Influence of season and latitude on the cutaneous synthesis of vitamin D3: Exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin". J Clin Endocrinol Metab. 67 (2): 273–8. doi:10.1210/jcem-67-2-373. PMID 2839537.
- ^ Lu, Z; Chen, TC; Holick, MF (1992). Influence of season and time of day on the synthesis of vitamin D3. In: Holick MF, Kligman A, eds. Proceedings of the Biologic Effects of Light Symposium. pp. 53–6.
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ignored (help) - ^ Clemens, TL; Adams, JS; Henderson, SL; Holick, MF (1982). "Increased skin pigment reduces the capacity of the skin to synthesize vitamin D". Lancet. 1 (8263): 74–6. doi:10.1016/S0140-6736(82)90214-8. PMID 6119494. S2CID 41818974.
- ^ Matsuoka, LY; Ide, L; Wortsman, J; MacLaughlin, JA; Holick, MF (1987). "Sunscreens suppress cutaneous vitamin D3 synthesis". J Clin Endocrinol Metab. 64 (6): 1165–8. doi:10.1210/jcem-64-6-1165. PMID 3033008.
- ^ a b Smith, EL; Walworth, NC; Holick, MF (1986). "Effect of 1 alpha,25-dihydroxyvitamin D3 on the morphologic and biochemical differentiation of cultured human epidermal keratinocytes grown in serum-free conditions". J. Invest. Dermatol. 86 (6): 709–14. doi:10.1111/1523-1747.ep12276343. PMID 2423618.
- ^ Pèrez, A; Chen, TC; Turner, A; Raab, R; Bhawan, J; Poche, P; Holick, MF (1996). "Efficacy and safety of topical calcitriol (1,25-dihydroxyvitamin d3) for the treatment of psoriasis". Br J Dermatol. 134 (2): 238–46. doi:10.1111/j.1365-2133.1996.tb07608.x. PMID 8746336. S2CID 24213908.
- ^ Adams, JS; Singer, FR; Dacad, MA; Sharma, OP; Hayes, MJ; Vouros, P; Holick, MF (1985). "Isolation and structural identification of 1,25-dihydroxyvitamin D3 produced by cultured alveolar macrophages in sarcoidosis". J Clin Endocrinol Metab. 60 (5): 960–6. doi:10.1210/jcem-60-5-960. PMID 2984238.
- ^ Schwartz, GG; Whitlatch, LW; Chen, TC; Lokeshwar, BL; Holick, MF (1998). "Human prostate cells synthesize 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3". Cancer Epidemiol Biomarkers Prev. 7 (5): 391–5. PMID 9610788.
- ^ Holick, MF (2004). "Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease". Am J Clin Nutr. 80 (6): 1678S–88S. doi:10.1093/ajcn/80.6.1678s. PMID 15585788.
- ^ Farraye, FA; Nimitphong, H; Stucchi, A; Dendrinos, K; Boulanger, A; Vijjeswarapu, A; Tanennbaum, A; Biancuzzo, R; et al. (2011). "Use of a novel vitamin D bioavailability test demonstrates that vitamin D absorption is decreased in patients with quiescent Crohn's disease". Inflamm Bowel Dis. 17 (10): 2116–21. doi:10.1002/ibd.21595. PMID 21910173. S2CID 4940789.
- ^ Tangpricha, V; Koutkia, P; Rieke, SM; Chen, TC; Perez, AA; Holick, MF (2003). "Fortification of orange juice with vitamin D: a novel approach for enhancing vitamin D nutritional health". Am J Clin Nutr. 77 (6): 1478–83. doi:10.1093/ajcn/77.6.1478. PMID 12791627.
- ^ Wortsman, J; Matsuoka, LY; Chen, TC; Lu, Z; Holick, MF (2000). "Decreased bioavailability of vitamin D in obesity". Am J Clin Nutr. 72 (3): 690–3. doi:10.1093/ajcn/72.3.690. PMID 10966885.
- ^ Heaney, RP; Davies, KM; Chen, TC; Holick, MF; Barger-Lux, MJ (2003). "Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol". Am J Clin Nutr. 77 (1): 204–10. doi:10.1093/ajcn/77.1.204. PMID 12499343.
- ^ a b David Armstrong (September 26, 2018). "The Child-Abuse Contrarian". The New Yorker. Retrieved 2018-09-30.
- ^ Szabo, Liz (2018-08-18). "Vitamin D, the Sunshine Supplement, Has Shadowy Money Behind It". New York Times. Retrieved 2018-10-07.
- ^ Jenifer McKim (March 13, 2015). "Boston University researcher draws fire for claiming some broken bones caused by rare disease, not abuse". The Boston Globe. Retrieved 2017-11-25.
- ^ Shawn Cabbagestalk (January 11, 2018). "Midlands father charged with abusing infant daughter who suffered permanent brain damage". WCBD News 2. Retrieved 2018-09-30.
- ^ a b "Boston Hospital Reports Disciplining of Child Abuse Skeptic". Medscape. Retrieved 2019-08-02.
- ^ a b c Armstrong, David (2019-07-24). "Boston Hospital Reports Disciplining of Renowned Child Abuse Skeptic". ProPublica.
- ^ Szabo, Liz (18 August 2018). "Vitamin D, the Sunshine Supplement, Has Shadowy Money Behind It". The New York Times.
- ^ "Paper recommending vitamin D for COVID-19 retracted four years after expression of concern". 24 June 2024.
- ^ "The UV advantage - biography - awards". Archived from the original on 2011-09-03.
- ^ "DSM Nutrition Award 2009 presented to Michael Holick and Heike Bischoff-Ferrari". Archived from the original on 2013-03-12.
- ^ "American Association for Clinical Chemistry - 2010 Van Slyke Award".
- ^ "2009 Linus Pauling Institute Prize Recipient". Archived from the original on 2012-03-07.
- ^ "Dr. Holick honored by Endocrine Society".
- ^ "BUSM professor receives 2011 ACN Communication Media Award". 23 November 2011.
- ^ Institute of functional medicine (2020). "About the Linus Pauling Award". Institute of Functional Medicine.