Lydia Villa-Komaroff

Lydia Villa-Komaroff

Portrait of Lydia Villa-Komaroff
Born September 7, 1947
Citizenship American
Fields Molecular Biology
Institutions Northwestern University
Alma mater Goucher College
Notable awards 2013 Woman of Distinction by the American Association of University Women
Spouse Anthony L. Komaroff

Lydia Villa-Komaroff (born September 7, 1947) is a molecular cellular biologist who currently works as a Chief Scientific Officer (CSO) and board member at Cytonome Incorporated.[1] Notably, she is the third Mexican American woman in the United States to receive a doctorate degree in the sciences (1975).[2] Her most notable discovery was in 1978 during her post-doctoral research, when she led a team that discovered how bacterial cells could be used to generate insulin.[3]

Life
Lydia Villa-Komaroff (As Told By Jo Handelsman)
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Villa-Komaroff was born on September 7, 1947, and grew up in Santa Fe, New Mexico. She was the eldest of six children and daughter of two teachers; her mother also worked as a social worker, and her father was also a part-time musician. Unlike most children, by the age of nine, Villa-Komaroff knew that she wanted to be a scientist after hearing her uncle discussing his work as a chemist.[3]

While in high school, she was awarded a scholarship from the National Science Foundation to attend a summer research program in a college in Tyler, Texas. After high school, she attended the University of Washington in Seattle as a chemistry major in 1965. There, she encountered an advisor who told her that “women do not belong in chemistry.” She switched majors, settling on biology. When her boyfriend, a 26-year-old medical student named Anthony Komaroff, moved to Washington, D.C., to join the Public Health Service in 1967, Villa-Komaroff followed. Her first choice of universities in the area, Johns Hopkins University, was not accepting female students at the time, so she transferred to its sister school, Goucher College in Maryland, where she was admitted as a junior. She married Anthony Komaroff in 1970 and moved with him to Boston.[2]

In Boston, Villa-Komaroff chose the Massachusetts Institute of Technology (MIT) for graduate work in molecular biology under Harvey Lodish and Nobel Laureate David Baltimore. Interestingly, as Villa-Komaroff told Weiler of The ASCB Post in an interview, she chose MIT because she wanted to learn to ask more questions and to be more assertive, two things she felt did not come naturally to her.[3] Her dissertation focused on protein translation in the polio virus. Throughout her time at MIT, Villa-Komaroff learned that “hard work can be fun,” and she dedicated her thesis to her colleagues and students (in particular, David Rekosh and David Housman) who she says “taught [her] to walk,” and her advisor who she says “taught [her] what it might be like to fly[3]”.

In 1973, she became a founding member of the Society for Advancement of Chicanos and Native Americans in Science (SACNAS)[4]

She completed her PhD at MIT in cell biology in 1975. She then went to Harvard to conduct her postdoctoral research for three years, focusing on recombinant DNA technology, under the supervision of Fotis Kafatos and Tom Maniatis. When Cambridge banned such experiments in 1976, citing worries about public safety and the chance of unintentionally creating a new disease, Villa-Komaroff moved to Cold Springs Harbor.[2] While at Cold Springs Harbor, she experienced repeated failures of her experiments; however, these disappointments taught her that “most experiments fail, and that scientists must accept failure as a part of the process[3]”. Villa-Komaroff felt that these failures aided in her biggest victory: six months after she was able to return to Harvard (once the ban on recombinant DNA experiments was lifted in 1977), where the success with insulin came after only 6 months.[3]

Upon returning to Harvard, Villa-Komaroff joined an insulin cloning team headed by Nobel Laureate Walter Gilbert. In early 1978, she was the first author of a landmark research report showing that bacteria could be induced to make proinsulin- the first time a mammalian hormone was synthesized by bacteria.[2]

Later in the same year, she joined the faculty of the University of Massachusetts Medical School (UMMS), where she was a professor for six years before being granted tenure. The following year, she left for a position at Harvard Medical School with a lighter teaching workload and more research opportunities including her research on transforming growth factor- α and epidermal growth factor during fetal and neonatal development published in 1992 and 1993. There, she continued to establish her name in molecular biology, and in 1995 a television documentary called "DNA Detective" featured her work on insulin-related growth factors. The segment ran as part of a six-part PBS series on women in science, under the umbrella title Discovering Women.

From 1998-2003, Villa-Komaroff was recruited to Northwestern University where she served as Vice President for Research of the university, and in 2003, she became the Vice President for Research and Chief Operating Officer of Whitehead Institute in Cambridge, Massachusetts.[5]

In 2005, she became chair of the board of a publicly traded biotech company, Transkaryotic Therapeutics, Inc., which was acquired by Shire Plc. In 2011, she became a member of the governing board of the Massachusetts Life Science Center.[6] Currently, Villa-Komaroff is the Chief Scientific Officer at CytonomeST, a company developing an optical cell sorter that supports rapid, sterile selection of human cells.[7]

Research Discoveries and Accomplishments

Villa-Komaroff's first publication, coauthored with Spector and Baltimore, was published in September 1975. Their study on the function of polyadenylic acid on RNA of the poliovirus provided data that poliovirus poly(A) is needed early on in the infection process. When poly(A) was removed from the RNA, infectivity of the poliovirus decreased to 2.25% of the untreated RNA; however, because the product produced by RNA with no ploy(A) tail was equally as effective as mRNA with a poly(A) tail, it was determined that poly(A) must be playing a role in encapsidaton of RNA or in RNA replication. Finally, it was concluded that Poly(A)-deficient poliovirus RNA molecules are not able to act as a template for 5’ terminus of the minus strand, and thus are unable to initiate an infection[8]

In October 1975, Villa-Komaroff, Guttman, Baltimore, and Lodish published a paper on the complete translation of poliovirus RNA in a eukaryotic cell-free system. In the experiment, only cells infected with the 35S viral RNA were found in cells infected with the poliovirus. From this RNA, it was determined that the poliovirus, like most eukaryotic RNAs, only has a single initiation site responsible for protein synthesis. It was also determined that host cell enzymes are utilized by the poliovirus for cleavage.[9]

Cancedda, Villa-Komaroff, Lodish, and Schlesinger also published a paper in October 1975. Their paper was on initiation sites for translation of the sindbis virus 42S and 26S mRNAs. Studies led to the conclusion that 26S RNA contains at least one initiation site, typical of eukaryotic mRNA; however, the 42S sindbis mRNA is a novel type of eukaryotic mRNA- it has two protein synthesis initiation sites, although it was unclear if the second site functions in the infected cell.[10]

In August 1978, Villa-Komaroff, Efstratiadis, Broome, Lomedico, Tizard, Naber, Chick, and Gilbert published one of the most pivotal findings in cellular biology- a bacterial clone capable of synthesizing proinsulin. Strain of Escherichia coli capable of producing proinsulin was designed. The gene carrying proinsulin (from rat insulin I) was cloned into the Pst site of the pencillinase gene. Resultantly, the insulin sequence was expressed as a fusion protein that yields both insulin and penicillinase. Polypeptidyl folds were also mapped in addition to the amino acid residue sequence so as to reveal insulin’s antigenic shape. Additionally, a method was developed that allows the expression and secretion of any eukaryotic protein, given that another protein serves as the carrier.[11]

In December 1986, Wentworth, Schaefer, Villa-Komaroff, and Chirgwin published their results on the investigation into characterizing two nonallelic genes that encode for mouse preproinsulin. Cloned genes showed nearly identical arrangement of exons and introns, and the genes additionally showed conservation of nucleotide sequence. Rat and mouse preproinsulin I genes are concluded to be homologous throughout their entire length. Rat and mouse preproinsulin II genes are concluded to be homologous throughout the entire 5’ region of sequence that was available, up until approximately 500 base pairs before the site of transcription.[12]

In June 1989, Gross, Halban, Kahn, Weit, and Villa-Komaroff published a paper titled “Partial diversion of a mutant proinsulin (B10 aspartic acid) from the regulated to the constitutive secretory pathway in transfected AtT-20 cells.” In order to investigate the role of a point mutation in the insulin gene that results in hyperproinsulinemia in type II diabetes patients, the mutation that causes hyperproinsulinemia was induced in rat insulin II gene. The induced mutation yielded an increase in proinsulin compared to insulin and rapid release of the newly synthesized proinsulin. Mutant cells also did not store or release the prohormone, even with stimulation. This failure to release the prohormone showed that the mutant prohormone is released via the constitutive secretory pathway instead of the regulated pathway. Control cell transfected with the native insulin gene upheld previous study findings that AtT-20 cells transfected with the human insulin gene can process proinsulin correctly through the regulated secretory pathway.[13]

The following month, in July 1989, Yankner, Dawes, Fisher, Villa-Komaroff, Oster-Granite, and Neve published their findings regarding Alzheimer’s and the neurotoxicity of the amyloid precursor. For cells they had transfected with PC12-AB1 (pheochromocytoma -Amyloid beta) and treated with neural growth factor, growth of neuritis initially occurred; however, after three to four days, neuritic process growth slowed, vacuolar inclusions formed, somas swelled and became granular, and then the cells died. Cells treated with antibodies directed against two different domains of AB-1 amyloid polypeptide showed moderate viability while those treated with AB1-conditioned media and an antibody for cell adhesion molecule had no change to neurotoxicity. The results showed that AB1 fragment of amyloid precursor is neurotoxic.[14]

Five months later, in December 1989, Gross, Villa-Komaroff, Kahn, Weir, and Halban published another paper about proinsulin titled “Deletion of a highly conserved tetrapeptide sequence of the proinsulin connecting peptide (C-peptide) inhibits proinsulin to insulin conversion by transfected pituitary corticotroph (AtT20) cells.” Connecting peptide (C-peptide) of proinsulin has a highly conserved peptide sequence in all proinsulins except for that found in hagfish; the sequence is hydrophilic. Experimentation with C-peptide and the highly conserved sequence revealed hat C-peptide is not involved in intracellular trafficking as proinsulin lacking C-peptide can still be correctly targeted to secretory granules; however, a single amino acid substitution yields a large amount of nonprocessed proinsulin that is not regulated and deviates from the regulated constituted release pathway. Thus, the mutant proinsulin was not converted into native insulin. These results indicate that base deletions and substitution play a large role in the signaling and conversion of molecules. The deletion of the C-peptide sequence prevented the cleavage by the two endopeptidases secreted by pancreatic B-cells necessary for conversion to native insulin.[15]

In February 1990, Lamperti and Villa-Komaroff published an alternative method for generating subclones for dideoxy sequencing. Their methods utilized deletions by frequent-cutting restriction endonucleases for partial digestion of an M13 bacteriophage construct, followed by reparation, relegation, and transfection of the partially digested M13 vector and DNA into bacteria. The resultant plaques bared variable portions of inserts. The methods described by Lamperti and Villa-Komaroff can be controlled with greater ease and can produce a discrete series of double-stranded cuts. The experiment published in this paper, “Generation of deletion subclones for sequencing by partial digestion with restriction endonucleases,” demonstrated that the simple method is accurate enough to allow specific targeting of a fragment that is several kilobases in length with a small number of subclones. The only drawback of the described protocol is a higher background of unusable, single-stranded templates that must be eliminated through a series of screening steps; however, this protocol is forgiving of problems (contaminants, incomplete digestion) that can be crippling in other methods.[16]

The following year in February 1990, Lamperti, Rosen, and Villa-Komaroff published their research on Vasoactive Intestinal Polypeptide (VIP) in rat and mouse (“Characterization of the gene and messages for vasoactive intestinal polypeptide (VIP) in rat and mouse”). The experiment, focusing on VIP expression, noted that human and mouse VIP are nearly identical in organization and the exons encoding neuorpeptides are amongst the most highly conserved portions of the gene. Because cDNA from a VIP-producing human neuroblastoma can code for VIP and for PHI-27, both of which have similar actions, the splicing for these genes was monitored. It was discovered that the arrangement of the sites for splicing for both VIP and PHI exons would allow removal of either exon sequence from a transcript while leaving the reading frame of the remaining message intact. While previous scientists have theorized that the exons could function as separate units, no evidence was found to support this. Lastly, Lamperti, Rosen, and Villa-Komaroff claimed that the search for VIP in non-neuronal cells was inconclusive and that all positive and negative results demonstrated the value of utilizing oligonucleotide-directed RNase H digestion for identity of bands in Northern blors hybridizations.[17]

In July 1991, Smith, Villa-Komaroff, Weir, and Bommer-Weir investigated the effects of enhanced insulin-like growth factor I gene and its expression in regenerating rat pancreas (“Enhanced insulin-like growth factor I gene expression in regenerating rat pancreas”). Male rats were given a 90% pacreatectomy to test Insulin Growth Factor I (IGF-1) mRNA expression as a response. IGF-1 mRNA was found to be local to capillary endothelieal cells in the operative and in the control rats. There was also no pancreatic endothelial cell differences in regards to IGF-1 levels between normal and surgical rats; however, levels of IGF-1 increased in arterial endothelial cells in the surgical rats after the operation, and mild hyperglycemia occurred after pancreatectomy. IGF-1 levels were found to be associated with pancreatic growth, and the majority of its expression is found within the pancreas in proliferating ductile epithelial cells and surrounding connective tissue cells. This data indicates that IGF-1 may play an important role in the regeneration of the pancreas either by autocrine or paracrine mechanisms to stimulate either DNA synthesis or proliferation in ductules.[18]

In 1992, Yeh, Rosen, and Villa-Komaroff published their findings on “Messenger ribonucleic acid for transforming growth factor- α, but not for epidermal growth factor, is expressed in fetal and neonatal mouse brain.” Prior to their experiment, little was known concerning Transforming Growth Factor- α in fetal and neonatal tissues. The presence of TGF- α mRNA would indicate that an autocrine or paracrine role is played for this growth factor in brain development. No epidermal growth factor (EGF) was observed in a developmental series in the brain, as confirmed by polymerase chain reaction-amplified DNA. Yeh, Rosen, and Villa-Komaroff came to the conclusion that fetal and neonatal expression of TGF- α mRNA is important in both the developing and mature mouse brain. EGF mRNA was not expressed. TGF- α expression was found in fetal and neonatal murine brain. TGF- α mRNA was expressed in all stages that were studied, beginning at embryonic day fourteen. The most probable reason for this finding is that TGF- α is a physiologic factor that acts as either the autocrine or paracrine ligand to the EGF receptor in mouse brain. These results also indicated that TGF- α mRNA is important in utero and postpartum too.[19]

The following year in May 1993, Yeh, Osathanondh and Villa-Komaroff published a further study on TGF-1 and EGF in an article titles “Expression of messenger ribonucleic acid for epidermal growth factor receptor and its ligands, epidermal growth factor, and transforming growth factor- α, in humans first- and second-trimester fetal ovary and uterus.” EGF receptor mRNA expression was present in all stages of fetal ovarian and uterine development, and both EGF and TGF- α mRNA expression was present in fetal development at all stages tested (10, 15, 19, and 22 weeks of gestation). Only EGF was expressed in fetal uterine tissues. This data showed that wide distribution of EGF receptors exists in human fetal tissues. EGF also appears to be a regulator of ovarian function and may play a critical role in the growth and development of both the ovary and the ovarian cell.[20]

One of the last papers published before Villa-Komaroff switched to industry was written by Tolentino and Villa-Komaroff on the “Regulation of vasoactive polypeptide and galanin mRNA stabilities.” The objective of this study was to determine the stabilities of VIP and galanin mRNAs in a human neuroblastoma cell line and to determine if post-transcriptional regulation of VIP and galanin mRNA stability was taking place that altered steady-state mRNA levels. It was found that after PMA (a phorbol ester) treatment, the difference in induction of VIP precursor hnRNA and VIP mRNA indicated that nuclear mechanisms could not entirely account for the extent of VIP mRNA induction. PMA treatment also resulted in the stabilization of VIP mRNA as revealed by the pattern of VIP mRNA degradation after actinomycin D treatment; however, PMA-induced VIP mRNA stabilization was only witnessed after actinomycin D-induced transcriptional arrest, and stabilization of VIP mRNA was not witnessed after transcriptional arrest by DRB. Based on these results, Tolentino and Villa-Komaroff concluded that PMA-stimulation is insufficient to ensure VIP mRNA stabilization.[21]

Awards & Honors

Past Positions

Current Positions

References

  1. ↑ 1.0 1.1 Shury, N (4 Apr 2014). "Hooray for women in STEM! Meet Lydia Villa-Komaroff 2013 Women of Distinction". American Association of University Women. Retrieved 7 Nov 2014.
  2. ↑ 2.0 2.1 2.2 2.3 Lydia Villa-Komaroff. Independence (KY): Gale, Cenage Learning. 2014. Retrieved 11 Mar 2014.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Weiler, N (30 Jul 2014). "Lydia Villa-Komaroff Learned in the Lab "What It Might Be Like to Fly"". The ASCB Post. Retrieved 7 Nov 2014.
  4. ↑ "Education, Preparation & Passion: Lydia Villa-Komaroff, Ph.D.". Color Magazine. Retrieved 11 Mar 2014.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 5.10 5.11 5.12 5.13 5.14 5.15 "Villa-Komaroff to Present SDI and Five Colleges Distinguished Lecture". University of Massachusetts Amherst. 27 Mar 2014. Retrieved 7 Nov 2014.
  6. ↑ "6. Executive Profile: Lydia-Villa-Komaroff Ph.D". Bloomsberg Businessweek. 2014. Retrieved 11 Mar 2014.
  7. ↑ "7. Leadership: Management". CytonomeST. 2014. Retrieved 11 Mar 2014.
  8. ↑ Spector DH, Villa-Komaroff L, Baltimore D. (Sep 1975). "Studies on the function of polyadenylic acid on poliovirus RNA.". Cell. 6 (1): 41–4. doi:10.1016/0092-8674(75)90071-9.
  9. ↑ Villa-Komaroff L, Guttman N, Baltimore D, Lodish HF. (Oct 1975). "Complete translation of poliovirus RNA in a eukaryotic cell-free system." (PDF). Proceedings of the National Academy of Sciences of the United States of America. 10: 4157–61.
  10. ↑ Cancedda R, Villa-Komaroff, L, Lodish HF, Schlesinger M. (Oct 1975). "Initiation sites for translation of sindbis virus 42S and 26S messenger RNAs.". Cell. 6 (2): 215–22. doi:10.1016/0092-8674(75)90012-4.
  11. ↑ Villa-Komaroff L, Efstratiadis A, Broome S, Lomedico P, Tizard R, Naber SP, Chick WL, Gilbert W. (Aug 1978). "A bacterial clone synthesizing proinsulin.". Proceedings of the National Academy of Sciences of the United States of America. 75 (8): 3727–31. doi:10.1073/pnas.75.8.3727. PMC 392859. PMID 358198.
  12. ↑ Wentworth BM, Schaefer IM, Villa-Komaroff L, Chirgwin JM. (Dec 1986). "Characterization of the two nonallelic genes encoding mouse preproinsulin". Journal of Molecular Evolution. 23 (4): 305–12. doi:10.1007/bf02100639.
  13. ↑ Gross DJ, Halban PA, Kahn CR, Weir GC, Villa-Komaroff L. (1 Jun 1989). "Partial Diversion of a mutant proinsulin (B10 aspartic acid) from the regulated to the constitutive secretory pathway in transfected AtT-20 cells". Proceedings of the National Academy of Sciences of the United States of America. 86 (11): 4107–11. doi:10.1073/pnas.86.11.4107.
  14. ↑ Yankner BA, Dawes LR, Fisher S, Villa-Komaroff L, Oster-Granite ML, Neve RL. (28 Jul 1989). "Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer’s disease". Science. 245 (4916): 417–20. doi:10.1126/science.2474201.
  15. ↑ Gross DJ, Villa-Komaroff L, Kahn CR, Weir GC, Halban PA. (25 Dec 1989). "Deletion of a highly conserved tetrapeptide sequence of the proinsulin connecting peptide (C-peptide) inhibits proinsulin to insulin conversion by transfected pituitary corticotroph (AtT20) Cells." (PDF). The Journal of Biochemistry. 264 (36): 21486–90.
  16. ↑ Lamperti ED, Villa-Komaroff L. (Feb 1990). "Generation of deletion subclones for sequencing by partial digestion with restriction endonucleases.". Analytical Biochemistry. 185 (1): 187–93. doi:10.1016/0003-2697(90)90278-h.
  17. ↑ Lamperti ED, Rosen KM, Villa-Komaroff L. (Feb 1991). "Characterization of the gene and messages for vasoactive intestinal polypeptide (VIP) in rat and mouse.". Molecular Brain Research. 9 (2): 217–31. doi:10.1016/0169-328X(91)90005-I.
  18. ↑ Smith FE, Rosen KM, Villa-Komaroff L, Weir GC, Bommer-Weir S. (Jul 1991). "Enhanced insulin-like growth factor I gene expression in regenerating rat pancreas.". Proceedings of the National Academy of Sciences of the United States of America. 88: 6152–6. doi:10.1073/pnas.88.14.6152. PMC 52040. PMID 1712481.
  19. ↑ Yeh J, Rosen KM, Villa-Komaroff L. (Jul 1992). "Messenger ribonucleic acid for transforming growth factor-α, but not for epidermal growth factor, is expressed in fetal and neonatal mouse brain.". American Journal of Obstetrics and Gynecology. 167 (1): 242–5. doi:10.1016/s0002-9378(11)91666-4.
  20. ↑ Yeh J, Osathanondh R, Villa-Komaroff L. (May 1993). "Expression of messenger ribonucleic acid for epidermal growth factor receptor and its ligands, epidermal growth factor and transforming growth factor-α, in humans first- and second- trimester fetal ovary and uterus.". American Journal of Obstetrics and Gynecology. 168 (5): 1569–73. doi:10.1016/s0002-9378(11)90800-x.
  21. ↑ Tolentino PJ, Villa-Komaroff L. (1996). "Regulation of vasoactive intestinal polypeptide and galanin mRNA stabilities.". Molecular Brain Research. 39: 89–98. doi:10.1016/0169-328x(96)00004-6.
  22. ↑ Stange MZ, Oyster CK, Sloan JE. (2011). Encyclopedia of Women in Today's World. Thousand Oaks (CA): Sage Publications, Inc. p. 151.
  23. ↑ "Lydia Villa-Komaroff Among 100 Most Influential Hispanics in America.". Whitehead Institute of Biomedical Research. 16 Oct 2003. Retrieved 11 Mar 2014.
  24. ↑ Vitetta ES. (2011). American Women of Science Since 1990. Santa Barbara (CA): ABC-CLIO, LLC. p. 941. Retrieved 11 Mar 2014.
  25. ↑ 25.0 25.1 25.2 25.3 25.4 25.5 25.6 "Board of Directors.". Massachusetts Life Sciences Center. 2014. Retrieved 7 Nov 2014.
  26. ↑ Molina J. (7 Jan 2009). "Breaking Barriers: World-Renowned Molecular Biologist Blazes New Trails". Hispanic Business. Retrieved 11 Mar 2014.
  27. ↑ "Regis College announces two honorary degree recipients and commencement speaker". Regis College. 15 Apr 2010. Retrieved 11 Mar 2014.
  28. ↑ Lang M. (9 Jun 2011). "WEST honors four women technology leaders.". Boston Business Journal. Retrieved 11 Mar 2014.