BREAKING NEWS ITEMS [2002]

Kidney Precursor Cells Identified in Humans and Pigs

December 28, 2002; As reported in the January 2003 issue of Nature Medicine, Israeli researchers have grown functioning kidneys in mice, a feat that could lead to the production of kidneys in humans, eliminating the need for transplants! The team inserted specific stem cells called, Kidney Precursor Cells from humans and pigs into mice. Both types of tissue grew into "perfectly formed functional kidneys the size of normal mouse kidneys." The kidneys actually produced urine and were sustained by blood vessels.

[ Editor's Note: Does anyone know if there are other organ precursor cells, like lung, heart, liver, etc.?]

Benjamin Dekel[1], Tatyana Burakova[1], Fabian D. Arditti[1], Shlomit Reich-Zeliger[1], Oren Milstein[1], Sarit Aviel-Ronen[3], Gideon Rechavi[3, 4], Nir Friedman[5], Naftali Kaminski[3], Justen H. Passwell[2], and Yair Reisner[1], "Human and Porcine Early Kidney Precursors As a New Source for Transplantation," Nature Medicine (December 23, 2002).

ABSTRACT:

Kidney transplantation has been one of the major medical advances of the past 30 years. However, tissue-availability remains a major obstacle. This can potentially be overcome by the use of undifferentiated or partially-developed kidney precursor cells derived from early embryos and fetal tissue. Here, transplantation in mice reveals the earliest gestational time point at which kidney precursor cells, of both human and pig origin, differentiate into functional nephrons and not into other, non-renal professional cell types. Moreover, successful organogenesis is achieved when using the early kidney precursors, but not later-gestation kidneys. The formed, miniature kidneys are functional, as evidenced by the dilute urine they produce. In addition, decreased immunogenicity of the transplants of early human and pig kidney precursors compared with adult kidney transplants is demonstrated in vivo. Our data pinpoint a window of human and pig kidney organogenesis that may be optimal for transplantation in humans.

1. Department of Immunology, Weizmann Institute of Science, Rehovot, ISRAEL
2. Department of Pediatrics, Sheba Medical Center, Tel Hashomer, ISRAEL
3. Functional Genomics Unit, Molecular Hemato-Oncology and Respiratory Medicine, Sheba Medical Center, Tel Hashomer, ISRAEL
4. Department of Pediatric Hemato-Oncology, Sheba Medical Center, Tel Hashomer, ISRAEL
5. School of Computer Science and Engineering, Hebrew University, Jerusalem, ISRAEL

Correspondence should be addressed to: Y Reisner. E-mail: yair.reisner@weizmann.ac.il.

Refs:

1. Reuters, "Kidneys Grown in Mice from Human Stem Cells," CNN (December 23, 2002).
2. "Israeli Team Grows Kidney in Mice," The Los Angeles Times, p. A18 (December 28, 2002).

Raelian Sect Says It Has Cloned the World's First Human Baby the Day After Christmas: No Evidence Yet

December 27, 2002; Hollywood, FL ( CNN) --- Biochemist, Dr. Brigitte Boisselier, Ph.D., CEO and Scientific Director of Clonaid, Inc. located in The Bahamas (no longer at a formerly secret laboratory in West Virginia after its location was discovered and raided by the FBI), announced at a beachfront hotel press conference in Hollywood, FL (North of Miami) this morning that they have succeeded in cloning the first human baby, and that four more cloned babies are on the way in January or February (one in Northern Europe, two from Asia, and one other from North America). The first is a reportedly healthy 7-pound baby girl born by C-Section at 11:55 AM EST on Thursday, December 26, 2002 and code-named Eve (not her real name, presumably to protect her privacy) at an unknown location (presumably in the Eastern time zone but not in the US or Canada in a clear attempt to evade national or local laws against this practice by remaining outside of their jurisdiction) to a married (husband is said to suffer from a male infertility factor), 31-year-old American woman who effectively delivered her daughter as her genetically-identical twin (displaced in time)! No proof of this claim was provided at this press conference, but it was stated that objective forensic DNA evidence would be forthcoming within nine or ten days. Michael Guillen, Ph.D., has been chosen to provide this service, using two different laboratories simultaneously. Dr. Guillen will not accept any funds from Clonaid or its surrogates.

[ Editor's Speculation: The logistics may prove difficult for any attempt by the parents to gain US Citizenship for their daughter and/or to return with her to the US without being subjected to potential harassment by the INS, and to maintain their privacy while not filing a meretricious Birth Certificate containing the imprimatur of the Health Service of the Country-of-Birth (a genuine female "Clone Birth Certificate," I imagine, would have to list the Mother as "Father" as well as "Mother," no? which would sort of make it stand out in comparison with your garden variety certificate) with a US State Department Visa Application at their local US Embassy/Mission. It would not be surprising if President Bush's Daily Morning Brief in Crawford, TX did not already contain all their full names and their address in the US, since there are at least two different methods the CIA could use (if they were asked) to identify an American family abroad given that citizens always leave an "audit trail" of their travels whenever they legally leave or re-enter the US at an official port-of-entry. And if they were flagged as being "persons-of-interest," they would be immediately subjected to detention and the full force of the law. They could, in principle, risk having all their US assets confiscated, lose their privileges as US citizens, and/or be permanently deported for a felony, if they in fact did anything illegal, like making false statements or forged an official document, or surreptitiously crossed the border with an illegal alien (Jane Doe). I am not a lawyer, but I do know that a number of indigent women, who chose to deliver their baby at home (which is certainly not illegal), brought their newborn child into our hospital the next day or so to have it briefly examined by a pediatrician and to have the birth officially recorded, which was done at no cost to the Mother and essentially as a public service.]

REACTION TO THE NEWS RANGES FROM SKEPTICAL TO RIGHTEOUS INDIGNATION...

Prof. Alta Charo of the University of Wisconsin said it was "medical grandstanding." Dr. Robert Lanza, M.D., of Advanced Cell Technology in Worcester, MA, stated that such attempts are "ethically appalling, scientifically irresponsible, and medically dangerous; a backlash could cripple an area of medical research [ therapeutic cloning] that could serve millions of people." In Rome, fertility doctor Severino Antinori, M.D., OB/GYN, said that the Raelian claim "makes me laugh." [Dr. Antinori will make his own announcement about a male clone in January.] President Bush commented through Deputy White House Press Secretary Scott McClelland that "he believes, like most Americans, that Human cloning is deeply troubling, and he strongly supports legislation banning all human cloning." Religious opponents warn that "human cloning represents an attempt by scientists to put themselves on a par with God." The Catholic Church weighed in with the statement, "This announcement is an expression of a brutal mentality, lacking all ethical and human consideration," Joaquin Navarro-Valls, a Spokesman for the Vatican. Prof. Stanley M. Hauerwas, Department of Theological Ethics at Duke University said, "The very attempt to clone a human being is evil; the assumption that we must do what we can do is fueled by the Promethean desire to be our own creators." The GRG itself will prepare an Editorial on this topic only after the Raelians provide the public with forensic DNA evidence, given that they have no scientific/medical track record in this field, regardless of how one may feel about their theological credibility and/or their outrageous lifestyle. CNN and Fox News TV channels and other media have had a "field day" with this story for the past two days.

December 29, 2002; Prof. Leon Kass, Chairman of the President's Advisory Council on Bioethics, said that "The arguments... go beyond questions of concerns about safety and really add up to a deep and permanent objection to what these Raelians claim to have done." Ms. Claire Buchan, White House spokeswoman, said that "the announcement underscores the need for Congress to act in a bipartisan manner to ban human cloning."

_________________________________
* About 4.5 percent of all IVF or test-tube babies have significant congenital defects in comparison with a comparable sex-matched control group of 4,000 babies. The defects ranged from cleft pallets to life-threatening heart-valve or ventricular foramen abnormalities. One of the newest methods of assisted conception called Intracytoplasmic Sperm Injection (ISI) [in which a single sperm is mechanically injected directly into the egg, secondary to male factor infertility] had a 9 percent rate of congenital defects in a survey of 1,138 infants done in England and Australia.

Refs:

1. Clonaid.com.
This site is viewable in any of five different languages. Curiously, news on the English version is more up to date than the French version. Since Rael's native language is French (Parisian French, not French Canadian), does that tell you something their marketing plan to prospect for future customers?
2. Rael.org .
This website is viewable in 20 different languages! The Raelians claim 55,000 members in 84 countries; however, active members may be substantially fewer than that. The site opens with a wonderful Flash Animation of Rael's first encounter with a four-foot-tall alien while traveling in central France. Curiously, the narrator has a distinctly British accent. There doesn't seem to be a comparable version for this animation (in French) on the French-language site. Presumably the original alien spoke French, but this level of detail is not revealed. Even the creatures from Middle Earth spoke their own neological language (with a well-defined, consistent vocabulary and syntax) in The Lord of the Rings.
3. John-Thor Dahlburg, "Firm Says It Created First Human Clone: Although Skepticism Abounds, Scientists Don't Entirely Reject the Claim that a Religious Group Believing in UFOs May Have Produced 'Eve'," The Los Angeles Times, pp. A1, 13 (December 28, 2002).
4. Michael Ramirez, Political Cartoon, "Six Identical Clowns are Exiting from a Very Small Car with "Clonaid" Written on the Side Door," The Los Angeles Times, p. B23 (December 28, 2002).
5. Times Wire Reports, New York, "Company Hints It Has Produced Human Clone," The Los Angeles Times, p. A17 (December 27, 2002).
6. "Raelian Leader: Cloning First Step to Immortality," CNN (December 28, 2002).
7. Fox News (December 27, 2002).
8. NBC-TV (December 26, 2002).
9. AP, "Expert to Probe Claim of Cloned Human," The New York Times (December 28, 2002).
The attempt at proof [that Eve is a true clone] will be made quickly, promised free-lance TV journalist Dr. Michael Guillen, Ph.D. The former ABC-TV Science Editor said he had chosen an expert who will draw DNA samples from the Newborn and her Mother.
10. Malcom Ritter, Associated Press, "First Cloned Baby? Religious Cult Announces Birth of First Cloned Baby," ABC-TV (December 27, 2002).
11. Gina Kolata, "Experts Are Suspicious of Claim of Cloned Human's Birth," The New York Times (December 28, 2002).
12. "Cloning Claim Prompts Call for Ban," BBC (December 28, 2002).
13. Rick Weiss, Staff Writer, "An Uncertain Year for Cloning Laws," The Washington Post (December 26, 2002).
The first discussion we have seen of Sen. Bill Frist's, M.D. (R -TN), the new Senate Majority Leader replacing Trent Lott, position on cloning and the fact that he went to visit ACT in Worcester, MA personally two weeks ago.
14. AP, "Clerics Denounce Cloned Baby Claim," The Los Angeles Times, p. A14 (December 29, 2002).
15. Antonios Regalado, Laurie McGinley, and Sarah Lueck, "Cloning Claim Spurs Ethics Debate: Claim of Clone by Raelians Provokes Skepticism," The Wall Street Journal, pp. A3, 6 (December 30, 2002).
16. Mark Heinzl and Antonio Regalado, "Clonaid's Claim Raises Doubt, Envy of Rivals," The Wall Street Journal, pp. B1, 3 (December 30, 2002).
17. AP, "Cloned Girl Will Fly to U.S. Today, Firm Says," The Los Angeles Times, p. A15 (December 30, 2002).
The US FDA believes that its charter offers the Agency some jurisdiction over attempts to clone humans in this country (only with its permission, which it has not given) and so "it plans to investigate whether any portion of the Clonaid Project occurred within the U.S. with criminal prosecution as a potential outcome of its probe."
[ Editor's Note: To our knowledge, all Clonaid facilities, but not its clients, are currently located abroad. If this proves to be the case, the FDA's investigation will turn out to have been a waste of time. In any event, this point will soon become moot when the Mother of "Eve" and her husband are interviewed by the media and such FDA suspicions are obviated. Since she is flying [ CNN] into the US today, there will be a feeding frenzy of tabloid reporters and paparazzi waiting there, attempting to purchase an exclusive interview, as soon as the airport is identified, which is probably known to a sufficient number of insiders that it will be purchased and/or leaked in the next few days, if this hasn't happened already. At present, the location of the parents' home is ostensibly still a secret, even though I suspect that the US Government is fully aware of it, and has put the FBI and the Justice Department on notice.]
18. Onora O'Neill, "Reason and Passion in Bioethcis," Science, Vol. 298, No. 5602, p. 2335 (December 20, 2002).
"Prof. Kass, the Chairman of President George W. Bush's Council on Bioethics, offers a passionate polemic against current ways of thinking about reproductive technologies in Reference 19 below."
19. Leon R. Kass, Life, Liberty, and the Defense of Dignity: The Challenge for Bioethics (319 pp.; $26.95; ISBN 1-893554-55-4; Encounter Books, San Francisco, CA; 2002).
20. Wire Services listing of virtually all news about the topic of human cloning.
21. Clone Rights United Front by Mr. Randolfe H.Wicker, who promotes himself as the World's First Pro-Human Cloning Activist, active since 1997.
22. Letters to the Editor, "If This Child Is Truly a Clone...," The New York Times, p. A20 (December 31, 2002).
Prof. Rebecca Dresser's (3rd) Letter, Law and Ethics in Medicine at Washington University in St. Louis, MO (December 28, 2002) was well reasoned. The others either complained that "2 + 2 = 4" or proudly announced that "2 + 2 = 4." For example, "If God hadn't wanted us to clone humans, He wouldn't have given us the power to do it." That counterfactual fallacious presuppositional speculation falls in the same category as my Aunt Tillie's advice: "God never intended for us to go to the moon; we should have stayed home and watched television, like He meant us to." or Donald Duck's advice: "The day before a vacation should be a vacation," presumably to allow for more preparation time, but that makes all recursively-innumerable days vacation days, past and future, doesn't it?
23. December 31, 2002 ( Fox-TV News) Mr. Philip Reeker, spokesman for the US State Department said at a press briefing, "Regarding the hypothetical situation of cloning, this is a new situation." (Reporters could be heard laughing in the background.) "We don't yet know how US law applies to the question of citizenship [which is not automatically granted to a child born abroad just because the parent(s) are US citizens]. However, for the record, all passport applications are confidential," meaning that INS/State was not going to reveal the location of the parents of Eve to the reporters just because they wanted to know.
24. Jane Sutton, "Legal Guardian Sought for Clone in Florida Court," Alert Net; Reuters Foundation (December 31, 2002); Miami, FL -- An attorney has asked a Florida State Court to appoint a legal guardian for the baby girl [Eve] purported to be the first human clone, saying that "the infant is being exploited and may have suffered birth defects."
[ Editor's Note: Talk about a nightmarish jurisdictional problem for a Florida judge if Eve doesn't reside in that state.]
25. Rick Weiss, "Cloning a Previous Hoax?" The Washington Post (December 31, 2002).
David M. Rorvik [previously a science reporter for The New York Times and Time Magazine, so he had some credibility, but his credentials also included wide-eyed articles on psychic and faith healers and a passionate advocacy of the discredited anti-cancer drug Laetrile] wrote a book entitled In His Image: The Cloning of Man (J. B. Lippincott Company, Philadelphia, PA; 1978), which told the tale of an unnamed American millionaire (code-named Max) who presumably hired Mr. Rorvik to set up a lab on an unnamed Pacific island where a team of scientists succeeded in cloning Max after five years of effort, using a paid surrogate mother for the full-term birth. The book represented this story as fact with real names presumably replaced by pseudonyms to protect the innocent and a full scholarly bibliography of references to the scientific literature (of that time) --- not as fiction - but it was subsequently proven to be a fraud and a hoax in 1981 (not by DNA evidence, which didn't exist yet, but by a court-order for evidence in a legal ruling). Experts called the book "a case study in commercial exploitation."
[ Editor's Note: I happen to own an original copy of this now out-of-print book in my collection. What was especially galling was that it quoted one of my Professors at Stanford Medical School, Dr. Joshua Lederberg (Nobel Laureate), as saying (in 1962) that "There is nothing to suggest any particular difficulty about accomplishing [cloning] in mammals or man, though it will rightly be admired as a technical tour de force when it is first accomplished. It places man on the brink of a major evolutionary perturbation." as a way to gain credibility for the book.]
26. James (The Amazing) Randi, a well-known skeptic, professional magician, and debunker of psychics and frauds (Uri Geller, the infamous spoon-bending Israeli prestidigitator, as well as so- called "psychic surgeons" in the Philippines who purportedly performed surgery on patients removing diseased internal organs without breaking the external skin) points out that an "independent chain of custody" of blood and/or skin samples (with coded non-forgeable labels: "A," "B," "C," etc.) from the Mother and Eve need to be guarded scrupulously before being shipped to two independent forensic laboratories (that presumably will provide identical results for samples "A," "B," "C," "D," "E," etc. with other coded dummy samples randomly mixed in).or risk a new round of fraud. If samples are out-of-sight of the investigative team for even a minute, one may expect foul play assuming the perpetrators of fraud hope to succeed by "not getting caught." By the way, Randi apparently has little respect for Dr. Michael Guillen, Ph.D. who has a Doctorate in Physics, Mathematics, and Astronomy from Cornell University and has been designated by Clonaid to be an objective custodian for the validation process and who says that he has no financial connection to either Clonaid or The Raelian Sect. In fact, Randi has dealt with Dr. Guillen before, saying "because of his acceptance of Scientology, cults are right up his alley, and to put him in charge of this investigation is like putting the fox in charge of the hen house." And Guillen has a potential conflict-of-interest, as he is in the process of negotiating a documentary about the sect as an independent producer, even though he denies that this would be a conflict, as such.
26. Matt Ridley [author of Genome: The Autobiography of a Species in 23 Chapters (Harper Collins, New York; 2000)], "Biology's Chernobyl," The Wall Street Journal, p. A14 (December 31, 2002).
27. Michael Shermer [publisher of The Skeptic Magazine and Columnist for Scientific American], "Wake Up, Cloning's Day Has Come," The Los Angeles Times, p. B13 (January 2, 2003).
28. AP, Paris; FRANCE, "Parents of Cloned Baby Undecided on DNA Testing," USA (January 2, 2003).
29. Amanda Onion, "Put to the Test: Genetic Tests Could Resolve Cloned Baby Claim, But Are Not Foolproof," ABC News (January 2, 2003).
30. AP, Paris, FRANCE, "Clonaid Says Parents Balk at DNA Test," The Los Angeles Times, p. A13 (January 3, 2003).
31. Sharon Begley, "Eve May Be Offspring of a Very Long Line of Hoaxes," The Wall Street Journal, p. A7 (January 3, 2003).
32. Paris, FRANCE, "Clone Firm: Second Birth by Sunday," CNN (January 3, 2003).
A Broward County, Florida Circuit Court has set a hearing date of January 22nd for a lawsuit filed by Attorney Bernard Siegel who has asked that the court to appoint a legal guardian for Eve, the alleged clone (does the home of Eve or does the location of the announcement provide the court with jurisdiction?). If the Mother of Eve does not appear at the hearing on that date then the court could conceivably order that the baby be removed from the Mother, a highly-unlikely prospect, and custody given to foster parents, providing that they can find the baby, who may have been sequestered somewhere else by other family members in the mean time.
33.Catherine Bremer, "Second Cloned Baby Said Imminent, But No DNA Tests," Reuters (January 3, 2003).

Raelian Sect Says It Will Deliver the World's First Cloned Baby on Christmas Day

December 24, 2002 Montreal, Quebec, CANADA ( Reuters) The cult that believes in free love and also teaches that all life on Earth was created by intelligent extra-terrestrials said that "it may deliver the world's first cloned baby (a girl) by Christmas Day." Coincidentally, the woman whose cells were used for the purpose of the cloning procedure has also served as surrogate mother, carrying the birth to full term. Therefore, she will literally deliver a genetic copy of herself. Dr. Brigitte Boisselier, Ph.D. biochemist and a Bishop in the Raelian Religion (founded by 56 year-old Mon. Claude Vorilhon (Prophet Rael) French Canadian) and CEO and Scientific Director of their cloning effort through a company called Clonaid, Inc., said that ten human embryos were cloned last Spring with only five miscarriages occurring, leaving the December birth and four other cloned babies to be expected in early 2003. Diagnostic ultrasounds were not mentioned but are presumably being done on a regular basis. The announcement above was greeted with skepticism by experts in the field. See the announcement below by Dr. Severino Antinori, M.D. of Rome (November 26th) that he expects to deliver a cloned boy sometime in January.

Ref:

"Sect Says First Cloned Baby Due Soon," MSNBC News (December 19, 2002).
This web page contains a really superb Flash Animation explaining the difference between therapeutic cloning and reproductive cloning.

U.S. Launches Proteomics Initiative

NIH will spend $157 million over the next seven years to unlock the protein interactions that underlie a spectrum of hear, lung, blood, and sleep disorders.

Ref:

Science Designates siRNAs the Top Story of the Year

December 20, 2002; Molecular switches called small interfering RNAs or siRNA's have the potential to treat such diseases as HIV and cancer, since these molecules could, in principle, instantly shut off selected genes along our chromosomes.

Refs:

1. "Molecular Switches Top Science Story," The Los Angeles Times, p. A14 (December 21, 2002).
2. Jennifer Couzin, "Breakthrough of the Year: Small RNAs Make Big Splash," Science, Vol. 298, pp. 2296-7 (December 20, 2002).
3. Ken Barber, "Prescription RNA," MIT Technology Review, Vol. 105, No. 10, pp. 42- 8 (December 2002, January 2003).

New Stem-Cell Law Passed in Australia

December 13, 2002; Australia's Parliament this week approved a national stem-cell law that will harmonize a jumble of state and territorial rules. Researchers will be able to use existing human embryonic stem-cell lines and create new lines from excess embryos created for IVF prior to April 5, 2002. This gives researchers a sound ethical basis to go forward, said Dr. Martin Pera of Monash University.

Ref:

Stanford University Receives $12 Million Grant for Research on Stem Cells

December 11, 2002; Palo Alto, CA; Prof. Irving Weissman, M.D. who will direct the new Institute for Cancer/Stem-Cell Biology and Medicine at Stanford University Medical School, will use tens of stem cells arising from eggs with nuclear transplants in mice and in humans to investigate the genetics of chronic diseases, such as cancer, diabetes, heart disease, allergies, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS), and others. Dr. Weissman has campaigned in scientific-journal editorials and through the National Academy of Sciences to achieve consensus on a separate label to distinguish the work he proposes to do from either reproductive or therapeutic cloning. Technically, he is using nuclear transplantation technology to produce a set of embryonic stem-cell lines that exhibit a particular pathology. Under certain conditions, a blastocyst (early embryo) can be formed in culture using 20 or 30 enucleated eggs with a corresponding number of fibroblast (skin cell) nuclei inserted. "If one were to work by itself, you'd call that a clone, while if two or three work together, you ought to call that nuclear transfer."

Refs.:

1. Marilyn Chase, Antonio Regalado, and David Hamilton, "Full Disclosure: Stanford Unveils Stem-Cell Plans," The Wall Street Journal, pp. A1, B1, 3 (December 11, 2002).
2. Aaron Zitner, "Stanford to Create Institute for Embryonic Stem-Cell Research: Scientists Do Not Rule Out Using a Form of Human Embryo Cloning, But Other Ways Will Be Tried," The Los Angeles Times, pp. A1, 14 (December 12, 2002).
3. "Stanford Stem-Cell Project Draws Criticism: Debate Over What Constitutes Cloning," CNN (December 11, 2002).
4. Antonio Regalado and Tom Liskey, "Cloning Pioneer Abandons Project: New Job at Michigan State Wouldn't Permit Research To Create Human Embryos," The Wall Street Journal, p. B4 (November 11, 2002).
Dr. Jose B. Cebelli, 39, Argentine-born researcher with Advanced Cell Technology of Worcester, MA, will leave ACT to accept a faculty position at Michigan State University in East Lansing, MI. Robert Lanza, M.D., VP of ACT said that, "due to a shortage of funds, Dr. Cebelli's Therapeutic Cloning Project had been put 'on hold' since earlier this year." (By the way, this shockingly negative revelation would have not have been known had one not read to the end of the article, since it started off with all this positive spin on Cebelli's career move.) ACT competitor Infigen, Inc. of DeForest, WI has recently reduced its own work force, as has cloning- pioneer PPL Therapeutics. Geron, Inc. of Menlo Park, CA and Celera Genomics, Inc. have likewise fallen on hard times along with the rest of the Biotech Sector.
[ Editorial Remark: What do we have to do to get this promising field moving again? The commercial Therapeutic-Cloning-Research Sector does not appear to be failing, at this point, because of the efforts of its ideological adversaries in the Bush Administration or even the pending adverse regulatory legislation in the US Senate, but because of the failing economy which is hurting everyone. Hopefully, the (anonymous) donor who has promised to fund the Stem-Cell Research Institute at Stanford will hang in there for the long haul (5 - 10 years).]
5. "Cloned Cells May 'Re-Boot the Immune System: Tests on Cows Could Lead to 'Grow-Your- Own' Human Transplants," CNN (December 6, 2002).
Dr. Robert Lanza, M.D., Medical Director of Advanced Cell Technology in Worcester, MA, reported at the Third Annual Conference on Regenerative Medicine held in Washington, D.C. earlier this week that "cattle allowed to live natural lives can survive 24 years and longer. We found the oldest cattle we could, and we cloned them. Stem cells traveled throughout their blood and out-competed their older, native cells. If this approach were to work in humans, it could not only be used to treat cancer and immunodeficiencies, but to 're-boot' the immune system in patients with various autoimmune diseases (Multiple Sclerosis, Rheumatoid Arthritis, Juvenile Diabetes, Systemic Lupus Erythematosis (SLE), Inflammatory Bowel Disease, and others) ." Lanza, along with other scientists working in the field, fears that the US Congress may soon block this sort of research. One of two competing bills would ban all cloning research involving humans, while the second would allow this type of work to go on. But U.S. Federal policy, backed by President Bush, is to ban all Federal funding of such work, which scientists believe will definitely slow it down. "We're all a bit frustrated by the lack of progress We should have been on the verge of clinical trials by now, but we're not." Lanza said.
6. Dr. Michael West, CEO, ACT, "Scientists Rewind Aging Clock in Cells of Cloned Cows, Study Says," CNN (April 27, 2000).
7. "Bush Advisor's Slam Stanford's Stem Cell Research," CNN (December 20, 2002).
8. "Apology in Stem Cell Feud: Stanford Retracts Statement Viewed as Suggesting Presidential Panel Backs Cloning," The Los Angeles Times, p. A14 (December 21, 2002).
Dr. Leon Kass, Chairman of the President's Council on Bioethics, demanded and received a correction, explaining that, contrary to what was stated on Stanford's website regarding the announcement of the creation of a new Institute for Stem-Cell Biology and Medicine, "[The Council] does not endorse cloning for biomedical research, and that Stanford had tried to 'obfuscate' the nature of its potential experiments. It is unfortunate that Stanford and [Prof. Irving] Weissman have clouded the ongoing debate over stem cells by disputing that their work could result in cloned human embryos."
[ Editor's Note: Phrases like "could not result," "should not result," "will not result," or "shall not result" are very tricky in legalistic English. Because Stanford's new Institute intends to use private funding exclusively -- and has no plans to seek grant funding from NIH or other Federal agencies --- its research program would be sanctioned under current law (because there is, at present, no Federal law governing private ventures in this highly entrepreneurial area). However, stay tuned to learn what the newly-constituted US Senate has in store for Stanford and its ilk, when it returns to session in January.]
9. Constance Holden, "Stanford Gets Gift for New Institute," Science, Vol. 298, No. 5602, pp. 2307-8 (December 20, 2002).
Nobelist Prof. Paul Berg says "their goal is to raise $100 million to support research on genetically-based treatments for cancer, Parkinson's Disease, heart disease, and other illnesses."

IBM Builds 6 nm Transistor

December 9, 2002; IBM will announce next week in San Francisco that it has developed a transistor that is one-tenth the size of the smallest such device in use today at six nanometers.

Refs.:

1. IBM, Armonk, NY; "World's Smallest Transistor," The Wall Street Journal (December 9, 2002).
2. David M. Ewalt, "Big Step for Nanotech: IBM Builds Worlds Smallest Transistor, Which Will Lead to More Powerful Chips," Information Week, p. 30 (December 16, 2002).

Rat Genomics Almost Wins the Race

December 7, 2002; The draft rat genome is only a whisker behind the mouse. The International Rat Genome Sequencing Consortium announced on November 25th that it completed its own draft sequence. Dr. Howard Jacob, Director of the Human and Molecular Genetics Center at the Medical College of Wisconsin in Milwaukee said, "I love the mouse, but rats are better models for clinical pharmacology (like diabetes, kidney disease, hypertension, and many other diseases)." "The rat genome hasn't been analyzed yet; however, we do know that it is larger than the mouse genome but smaller than the human genome," said Prof. Richard Gibbbs, Director of the Genome Center at the Baylor College of Medicine in Houston, TX. "Having two rodent genomes and the human genome will be particularly helpful in interpreting and cross-checking the sequences from all three mammalian species."

Ref:

Rosie Mestel, "Research Wins in Genome Rat Race," The Los Angeles Times, p. A24 (December 7, 2002).

Mouse Genome Published on the Internet by the Public Genome Sequencing Consortium

December 5, 2002; According to Dr. Robert Waterston of Washington University in St. Louis, only 300 genes (about 1 percent) are unique to either the mouse or humans (30,000 genes are present in both mammals). The total amount of DNA in a mouse (2.5 Giga Base Pairs) is about 15 percent less than that of humans, not because they have fewer genes but because they have the have less "junk" DNA in which the genes are embedded. Admittedly, we don't know what junk DNA does. Indeed, a significant number of the 300 unique genes on the mouse side turn out to be specific for odors, not for long whiskers or tails, which are present in humans too but just not expressed in the same way. Obviously, smelling is a more critical sense for the survival of rodents than it is for primates. See today's issue of the journal Nature with one of the Abstracts cited below.

[ Editor's Note: Celera Genomics has sold subscriptions to its Mouse Genome Data Base for the last year-and-a-half to its paying customers. However, the public version of the mouse-genome sequence will be available free-of-charge to any investigator on the Internet. It would be of great interest if one of the Celera's customers came forward publically with their view of the value of paying for the privilege of having an early copy. For example, are the two versions nearly the same. The public version is essentially 95 percent complete as I understand. Does one or the other have more annotations that makes it more valuable?]

[ Editorial Remark: In any event, we consider this to be an important milestone for gerontology despite the fact that most of the scientists doing the work don't consider themselves gerontologists (but rather computational geneticists). Nor do most gerontologists even track this aspect of genetics, which they consider a branch of biology outside their field of interest! The conspicuous reason that this is a milestone is that the comparative genomics of all mammals from rodents to bats/dogs/cats/rabbits/pigs/goats/sheep/cows/horses/giraffes/elephants/whales and finally to primates will provide us for the first time with the protein data we need to understand and manipulate the two order-of-magnitude differential longevity phenotype expressed by these various mammalian genomes and anatomically where their annual "clocks" are expressed, presumably in the brain somewhere (maybe the anterior hypothalamus). Just as the SA Node and the AV Node are bundles of reverberating nerve fibers in the heart that clock the (milli-second time-constant) rhythm of the EKG (P-QRS-T) 24 hours-a-day for as long as we live (modulated by the Vegas Nerve and Sympathetic Fibers to allow for a slower heart rate when we're asleep and a faster one when we're running to catch a train, respectively), so must there be a diurnal clocking mechanism (pineal gland) that synchronizes the annual clock(s) that determine the precise onset of puberty (12 +/- 2 years) and andro/menopause (52 +/- 5 years) that ultimately leads to the no-less-real epiphenomena of aging, chronic disease, and death (Average Life Expectancy, as modulated by one's inherited genes, nationality, climate, nutrition, exercise, and life style (peace vs. war time, daily stress level, marriage, occupation, smoking, and other parameters of risk taking)).]

[ Editor's Note: After his talk, we asked our December Speaker, Dr. William A. Goddard, III, Charles and Mary Ferkel Professor of Chemistry, Material Science, and Applied Physics, and Director of the Materials and Process Simulation Center at CalTech to comment on how long he thought it might take us to understand the structure of the biochemical receptors on Embryonic Stem Cells that dictate how it could be that only 150 or so unique genes in mice that are not in humans, less than 1 percent leads them down an embryogenesis pathway to express the phenotype of "whiskers and tails" while we instead with a similar number of unique genes grow up without whiskers and tails but grow up to be six feet tall? He said, "That's a really tough problem (in comparison with what we've done during the last few years). It might take four or five additional years to figure that out!" We answered, "we'll check back with you in five years." ]
+++++++++++++++++++++++++++++++++++++++

The Mouse Genome Sequencing Consortium, "Initial Sequencing and Comparative Analysis of the Mouse Genome," Nature, Vol. 420, pp. 520-562 (December 5, 2002).

ABSTRACT:

The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure, and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.

Refs:

1. News Roundup, "Genetic Makeup of Mice Presents Insights for People," The Wall Street Journal, p. A1, D10 (December 5, 2002).
2. Rosie Mestel, "Of Mice and Men: We're Quite Similar, Genetically. Scientists Complete Map of the Rodent's Genome, Which Is Hailed As an Essential Research Tool," The Los Angeles Times, p. A1, 19 (December 5, 2002).
3. "Mice and Men Share 99 Percent of Their Genes," CNN (December 4, 2002)
4. Nicholas Wade, "At Genetic Frontier, the House Mouse Serves Humanity," The New York Times, p. D1, 3 (December 10, 2002).
5. For a Mouse Genome Informatics Database that compiles most information about the genetics of the standard laboratory mouse ( C57BL strain) click on The Jackson Laboratory in Bar Harbor, ME. This database has lists of known mouse genes and reports the work of nomenclature committees on how to refer correctly to mouse strains and provides an anatomical dictionary/browser ranging from fetogenesis to adulthood. The Fantom Consortium (Functional Annotation of the Mouse) has captured and decoded 61,000 transcripts (essentially the protein products of all the active genes in mouse cells). The Complex Traits Consortium's goal is to find out how mouse genes act in concert. So far, only about 5,000 genes have been mutated.by the International Mouse Mutagenesis Consortium. They plan to generate mouse strains with mutations in the remaining 25,000 genes soon. Lexicon Genetics, Inc. of Woodland, TX (North of Houston) has coverage for 59 percent of the genes that are active in stem cells. Lexicon is systematically disrupting genes in early embryonic stem cells to find out which embryos can then be grown into full pups and, therefore by complementarity, which mutations are lethal.
6. Elizabeth Pennisi, "Genomics: Sequence Tells Mouse, Human Genome Secrets," Science, Vol. 298, No. 5600, pp. 1863-4 (December 6, 2002).
7. Charley Rose PBS-TV Interview with Dr. Eric Lander, Director of the Whitehead Institute's Center for Genome Research at MIT (Monday, December 9, 2002; 11:30 PM PST).

Craig Venter Proposes to Develop an Artificial Organism

December 4, 2002; Drs. J. Craig Venter Director and Nobel-prize winner Hamilton Smith along with a 25-member team at the Institute for Biological Energy Alternatives in Rockville, MD were awarded a three-year $3 million dollar contract by the US DOE to design a novel form of life. They must produce a useful, self-replicating organism with a completely artificial genome capable of removing unwanted carbon or toxic materials from the environment or producing hydrogen for fuel.

Ref:

Eliot Marshall, "Venter Gets Down to Life's Basics," Science, Vol. 298, No. 5599, p. 1701 (November 29, 2002).

Lack of Stem Cells Slows Brain Repair in Huntington's Disease

November 30, 2002; Dr. Maurice A. Curtis of the University of Auckland in New Zealand has formulated a new hypothesis that there is an ongoing process of neurogenesis in all adult brains, which if not properly maintained leads to a global deficit, like Huntington's Disease. Proliferating Cell Nuclear Antigen (PCNA) which is a hallmark of dividing cells, along with a protein called Class III Beta-Tubulin, which is specific to nerve cells, is important in replenishing dead neurons. In Huntington's the brain apparently cannot generate new nerve cells fast enough to replace the dying ones.

Ref:

John Travis, "Slow Brain Repair Seen in Huntington's," Science News, Vol. 162, No. 21, p. 334 (November 23, 2002).

Upregulated p53 Mice Have Fewer Tumors - Normal Life Spans

November 30, 2002; A third copy of the endogenous p53 gene was inserted into mice who not only demonstrated enhanced activation of a p53 response to DNA damage, they developed significantly fewer tumors after exposure to carcinogens. Contrary to the findings at Baylor University in Houston, TX earlier this year, these super-p53 mice did not exhibit signs of premature aging. A good question would be, why didn't they exhibit a longer lifespan than controls, since mice are known for suffering a large number of tumors just before they die.

Refs:

1. Garcia-Cao, et al, EMBO Journal, Vol 21, No. 6225 (2002).
2. "Is More p53 Better?," Science, Vol. 298, No. 5597, p. 1301 (November 15, 2002).

Mechanism of CR Uncovered at Yale

November 29, 2002; As published in today's issue of Science, Rpd4, a histone deacetylase enzyme, is likely to be a key gene for longevity, according to Prof. Stewart Frankel of Yale University. Drosophila with lower levels of the enzyme lived [33 - 50] percent longer than controls. A CR diet leads to life extension of about 41 percent. The compound Phenylbutyrate is thought to target the Rpd3 enzyme and could be useful as a model for the development of drugs that inhibit this particular enzyme and provide benefits without having to endure the rigors of CR.

Blanka Rogina[1], Stephen L. Helfand[1], and Stewart Frankel[2]*,
"Longevity Regulation by Drosophila Rpd3 Deacetylase and Caloric Restriction,"
Science, Vol. 298, No. 5598, p. 1745 (November 29, 2002).
________________________
[1.] Department of Genetics and Developmental Biology,
School of Medicine,
University of Connecticut Health Center,
Farmington, CT 06030, USA;
[2.] Department of Pediatrics,
Boyer Center for Molecular Medicine,
Yale University School of Medicine,
295 Congress Avenue, New Haven, CT 06536, USA
. * To whom correspondence should be addressed:. E-mail: stewart.frankel@yale.edu.

ABSTRACT:

Genetic studies of single gene mutations are revealing mechanisms and pathways that regulate longevity across distant species (1). One such mechanism is an alteration in histone deacetylase activity. Abolishing expression of the Rpd3 deacetylase (2) or increasing expression of the Sir2 deacetylase (1) increases life-span in yeast; Sir2 mediates increased nematode longevity as well (1). Caloric restriction is an intervention that increases life-span in mammals, insects, nematodes, and yeast (1, 3). Although the molecular pathways underlying the response to caloric restriction are yielding to genetic analysis in yeast (1), there is little information on how this response is regulated in metazoans. We investigated the relationship between histone deacetylases, caloric restriction, and longevity in Drosophila.

Greatly reduced Rpd3 levels are lethal in Drosophila (4), but partial reduction of Rpd3 levels has not been evaluated for its effect on life-span. We found that males heterozygous for either a hypomorphic (partial loss-of-function) or null mutation of rpd3 have life-span extension of 33% and 41 to 47%, respectively (Fig. 1A). Females heterozygous for the hypomorphic allele have a 52% increase in life-span, whereas females carrying the null mutation have only modest changes in life-span (maximum but not median life-spans are increased). The presence of large increases in life-span for males carrying both types of allele indicates that the effect is specific to the rpd3 locus. The different results for females may indicate a greater sensitivity to the predicted lower levels of Rpd3 in individuals carrying the null mutation compared with individuals carrying the hypomorphic allele.

To further explore the parallels between life extension in yeast and Drosophila, we examined the effect of caloric restriction on normal-lived control and long-lived rpd3 mutants. Longevity is increased to approximately the same extent in control flies fed a low-calorie diet and rpd3 mutants fed a normal diet (Fig. 1B). In addition, caloric restriction of the rpd3 mutants shows no further extension of life-span (Fig. 1B). The lack of an additive increase in longevity is not due to a physiological cap for life-span extension, because rpd3 females that were kept as virgins did have a further extension of longevity [see (14) in supporting online material (SOM) (5)]. Furthermore, at least one other mutation in Drosophila, Indy, increases life-span to a greater extent (>90%) (6). It has previously been demonstrated that caloric restriction of flies leads to a moderate but significant down-regulation of Rpd3, analogous to the decreases obtained in heterozygotes carrying rpd3 mutations (7, 8). The data suggest that life-span extension by the rpd3 mutation is within a pathway related to caloric restriction.

Given the evidence connecting histone deacetylases to life-span extension, we wanted to determine whether Drosophila longevity was generally responsive to changes in histone acetylation. Increased acetylation (9) was achieved by mutating an independent locus, Su(var)2-101. This had virtually no effect upon life-span (5). The effects of Rpd3 therefore appear to be specific, mediated by its targeting to particular genes and/or histone residues. The life-span extension obtained by feeding the drug phenylbutyrate to adult Drosophila may operate by a similar mechanism (10).

Studies in yeast have implicated Sir2 as an important element in the life-extending effects of caloric restriction (1). We found that under our two life-extending conditions, rpd3 mutants fed normal food and wild-type flies fed low-calorie food, Sir2 expression was increased twofold (Fig. 1C). Our results highlight the conservation of longevity regulation across distant species boundaries and suggest a genetic pathway that begins with caloric restriction and proceeds to down-regulation of Rpd3, followed by Sir2-independent regulation of longevity effector genes (gene activation) and/or increased Sir2 levels and Sir2-dependent modulation of longevity effector genes (gene silencing).

Other Refs.:

1. CNN (November 27, 2002).
2. Reuters, "Enzyme May Be Key to a Longer Life," The Los Angeles Times, p. A37 (November 29, 2002).

First Human Clone To Be Born in January

November 26, 2002; Rome, ITALY (CNN) --
Dr. Severino Antinori, M.D. announced today that he with others will soon accomplish their goal of being the first to perform human cloning. A surrogate mother carrying a cloned baby is allegedly pregnant with a delivery date sometime next month (early January 2003) presumably in a country where it is not illegal. Three more surrogate mothers are also pregnant, and it is assumed that they will deliver at later dates. However, Dr. Antinori offered no proof for any of these extravagant claims.

Both Prof. Rudolf Janesch, Ph.D., of MIT and Robert Lanza, M.D., Vice President of Medical and Scientific Development of Advanced Cell Technology of Worcester, MA commented saying that Dr. Antinori is considered to be a fringe practitioner who has systematically ignored the warnings of the scientific community by conducting such irresponsible experiments apparently for his own personal edification.

The LA-GRG will prepare a detailed Editorial on the significance of this matter if and when Dr. Antinori and his anonymous colleagues publish their work in a respected, peer-reviewed scientific journal containing definitive DNA evidence to support their claims. The standard of proof for cloning was first established by Dr. Ian Wilmut when Dolly the sheep was cloned and DNA evidence was published in Nature shortly thereafter.

. Refs:

1. ABC-TV Local News, Tuesday, November 26, 2002; 4:00 PM PST.
2. CNN (November 27, 2002).
3. CNN (November 26, 2002).
4. Connie Chung, Interview, CNN (November 29, 2002).
5. Robin Marantz Henig, "Adapting to Our Own Engineering: Clones May Soon Be As Acceptable As Test-Tube Babies," Op-Ed Piece, The New York Times, p. A35 (December 17, 2002).
Antinori, Zavos, and the Raelians (Boisselier) are in a three-way race.

Stem-Cell Reviews in Curent Issue of JuveNews

November 25, 2002; JuveNews, published in the San Francisco Bay Area, provides current summaries on the biology of aging, youth, and rejuvenation. The Managing Editor is Mignon Fogarty, the Senior Science Editor is Dr. Gregory Frank, and the Business Editor is Brian Chiko. Click for more details .

Aging Linked to Apoptosis by Way of Sir-2 Gene

November 25, 2002; Prof. Leonard Guarente of MIT began studying a regulator gene called Sir2 in yeast more than 20 years ago. It is now known that Sir2 together with the vitamin co-factor NAD (strict dependence) deacetylases (removes an acetyl group from) a histone (a protein that binds to DNA) preventing transcription (silencing). Homologs of this gene are conserved in a variety of species from E. coli to C. elegans, to mice, and probably to humans. The NAD component is part of a feedback loop involving cellular mitochondria (metabolic rate). By the way, Caloric Restriction (CR) extends the lifespan of yeast and other organisms only so long as Sir2 products (Sirtuins) and NAD are both present. The human homolog of Sir2 is called Sirt1 and appears to prevent apoptosis in human cells by inhibiting the p53 gene that is heavily implicated in preventing cancer.

Ref:.

Jennifer Fisher Wilson, "Enzyme Role Found for Aging Gene: Two Labs Independently Discover the Mechanism for How Sir2 Extends Lifespan," The Scientist, Vol. 16, No. 22, pp. 36- 37 (November 11, 2002).

Stem Cells Repair Damaged Hearts

November 25, 2002; Experts estimate that 50 persons have received cell transplants in their hearts since the procedure was first attempted about ten months ago. There has been no reported uncorrectable toxicity, and many of the patients have improved significantly. Yet, no cause-and- effect relationship can be attributed to the stem-cell therapy, since these patients are generally very sick (with very low cardiac ejection fractions) and are undergoing a variety of interventions simultaneously, anyone of which could be responsible for their improvement. Dr. Francis Pagani of the University of Michigan, Dr. Philippe Menasche of the Georges Pompidou European Hospital in Paris, and Dr. Nabil Dib of the Arizona Heart Institute in Phoenix are all performing some of these trials on small numbers of patients, all of which leads to anecdotal reports of great promise. However, a major clinical trial must be started soon to gain acceptance for this treatment by the larger cardiology establishment. A planned trial involving 300 patients in Europe and North America will be performed under the direction of Dr. Manasche in Paris cosponsored by Genzyme Biosurgery, which developed the technique for growing the bone- marrow stem cells in culture. Hopefully, we will have some answers in about a year or so.

Ref:

Thomas H. Maugh, II, "For Damaged Hearts, Some Added Muscle," The Los Angeles Times, pp. F1,8 (November 25, 2002).

Human Clinical Trials of Caloric Restriction Planned by NIH

November 25, 2002; Dr. Donald K. Ingram, Acting Chef of the Laboratory of Experimental Gerontology at NIH has announced a multi-center trial of human Caloric Restriction to be conducted at Louisiana State University, Tuffs University in Massachusetts, and Washington University in St. Louis, Missouri Hopefully, we will establish a more rigorous means for determining whether a methodology that works for rodents and monkeys actually does work in people, given all the obvious constraints associated with human subjects in a long-term study. The only other rigorous investigation of human subjects was done by conscientious-objector volunteers during World War II that led us to the conclusion that such subjects become highly irritable and spent most of their time "reading cookbooks planing their meals for when the study would be over!"

Ref:

Bob Rosenblatt, "Eating Less for Longevity," The Los Angeles Times, pp. F1,4 (November 25, 2002).

Aging Well Runs in Families

November 22, 2002; Chicago, IL ( CNN); Children of centenarians are less likely to suffer from a number of cardiovascular diseases, according to a study presented Monday at the annual meeting of the American Heart Association. Click for more details .

VEGF Genetic Engineering for Angina

November 21, 2002; Chicago, IL (American Heart Association); In a clinical trial involving 71 patients with angina, injecting a Vascular Endothelial Growth Factor (VEGF) gene by way of an adenovirus (vector) into the heart muscle prompted patients to grow their own blood vessels and thereby bypass obstructed coronary arteries. However, opening the chest wall is such a traumatic surgical procedure by itself that a much less invasive technique threading a catheter into the heart for administration of the VEGF gene -- will be tried next.

Ref:

Ron Winslow, "Gene Therapy Bolsters Weak Heart," The Wall Street Journal (November 21, 2002).

Significant Side Effects in a Short-Duration Clinical Trial of hGH

November 13, 2002; Drs. Marc Blackman and Mitchell Harman have reported in today's issue of JAMA that Carpal Tunnel Syndrome, joint pain, swollen limbs, Diabetes Mellitus and other disturbances in blood sugar regulation appear at significantly higher rates than was previously expected under the controlled conditions of a 26-week clinical trial. The authors have therefore recommended that, for now, hGH for the elderly be restricted to rigorous clinical trials until more is known. However, Prof. Ronald Swerdloff of Harbor UCLA Medical Center said he has noticed "impressive improvements in the bodies and moods of growth-hormone-deficient patients after administration of hGH injections." On the other hand, he agrees that "although there could be substantial benefits to giving hGH to elderly patients, far more needs to be known before this treatment could be deemed safe for widespread use."

[ Editor's Note: Drs. Blackman, Harman, and Swerdloff have all been Guest Speakers to the GRG over the years.]

Refs:

1. Rosie Mestel, "Troubling Side Effects Found with Growth Hormone, The Los Angeles Times, p. A18 (November 13, 2002).
2. Marc R. Blackman, MD; John D. Sorkin, MD, PhD; Thomas Mnzer, MD; Michele F. Bellantoni, MD; Jan Busby-Whitehead, MD; Thomas E. Stevens, MD; Jocelyn Jayme, MD; Kieran G. O'Connor, MD; Colleen Christmas, MD; Jordan D. Tobin, MD; Kerry J. Stewart, EdD; Ernest Cottrell, BS; Carol St. Clair, MS; Katharine M. Pabst, CRNP, MPH; and S. Mitchell Harman, MD, PhD, "Growth Hormone and Sex Steroid Administration in Healthy Aged Women and Men: A Randomized Controlled Trial," JAMA,.Vol. 288, No. 18, pp. 2282-92 (November 13, 2002).

John Gearhart vs. Leon Kass on Stem Cells

The philosophical battle over stem-cell research (and cloning in particular) seems to be taking a nasty turn. In the most recent clash, prominent stem-cell scientist Prof. John Gearhart slammed bioethicist Prof. Leon Kass for suggesting that researchers who reject restrictions on research [therapeutic] cloning are "rogues and rascals." Kass is alleged to have said "The few rogues and rascals who won't live here [in the USA], we are well rid of." In rebuttal, Gearhart quoted Prof. Richard Feynman: "Philosophers say a great deal about what is absolutely necessary for science, and it is always, so far as one can see, rather naive and probably wrong."

Ref:

"Jabs on the Stem-Cell Front," Science, Vol. 298, No. 5596, p. 1169 (November 8, 2002).

U.N. Postpones Ban on Reproductive Cloning

November 8, 2002; France and Germany had recently urged the Legal Committee of the United Nations General Assembly to formulate a treaty to halt Human Reproductive Cloning immediately and take up a more controversial question regarding Therapeutic Cloning at a later time, but they were overruled by a U.S. end run that successfully postponed this urgently-needed ban for at least one more year. This maneuvering appears to be an instant replay of the US Senate Debate on the Brownback Bill earlier this year that led to a similar "stand off" with no laws passed at all. Conservative fundamentalists apparently prefer to see no laws regarding human cloning than to appear to endorse a distinction they find "morally abhorrent," i.e., Therapeutic Cloning, that might lead to the deliberate destruction of embryos, regardless of potential cures for Heart Disease, Cancer, Parkinson's Disease, or other degenerative diseases. [ Editorial Rhetoric: If a human embryo is to be considered a person (a tissue capable of being murdered), but obviously not a finger-nail clipping that can be safely disposed of without fear of prosecution, is having a period following intercourse (a "disappointed" uterus) the same as murder? Or is the "twinkle in a man's eye when he encounters a beautiful woman" the same as a person?]

Refs:

1. Maggie Farley, ""U.S. Puts Off U.N. Ban on Cloning," The Los Angeles Times, p. A3 (November 8, 2002).

The NEJM Prepares Physicians for Gene-Based Medicine

1. Harold Varmus, "Getting Ready for Gene-Based Medicine," The New England Journal of Medcine, Vol. 347, No. 19, pp. 1526-7 (November 7, 2002).
2. Alan E. Guttmacher and Francis S. Collins, "Genomic Medicine: A Primer," The New England Journal of Medicine, Vol. 347, No. 19, pp. 1512-20 (November 7, 2002).

Delta-1 Protein Amplifies Cord Blood Stem Cells by 14 Times in Culture

November 1, 2002; Researchers from the Fred Hutchinson Cancer Research Center and the University of Washington in Seattle have used a signaling protein in the notch pathway called Delta-1 to amplify stem-cell proliferation of CD34+CD38- lines without inducing premature differentiation by 14 times compared to controls. This cell line is important in transplantation work, since they're so primitive, they're less likely to induce GVH (Graft vs. Host) or rejection by host WBCs than more highly-differentiated cells might.

Refs:

1. Irwin D. Bernstein, et al., Journal of Clinical Investigation (October 15, 2002).
2. Nathan Seppa, "Blood Booster: Growth Signal Shifts Cord Stem Cell into High Gear," Science News, Vol. 162, No. 17, pp. 161-2 (October 26, 2002).

[ Editorial Remark: I don't wish to pour cold water on this new discovery, but we must try to put the announcement in better perspective. All regulatory gene products are proteins that cluster within the cell into serial/parallel networks (like an arrangement of dominos ready to fall over). They form long cascades as they fall, whenever triggered by a precise external stimulus, e.g., clotting is triggered by a cut in the integument or other lesion to our internal epithelium . Yet, the clotting cascade has more than a half-dozen factors that must all line up perfectly to accomplish the task. Organizing the genes and their products into ordered networks is critical to our understanding of the functions they accomplish and at which points interventions make sense and where they don't. "Delta-1" is just one protein that may participate in a complex pathway for proliferation/apoptosis. We need to know all the intracellular-communication signals that determine the architecture of a tissue/organ. Only then can we understand how to intervene in the process. Remember that there are "No old caterpillars," just as there are "No old tadpoles." The genetic machinery for butterflies (following Juvenile Growth Hormone and Metamorphosis/Chrysalis Formation) and frogs (following another sort of transformation), respectively, are all in place "waiting in the wings" as it were, waiting to trigger the next stage in the Life History of the organism.. When the complete human proteome is completed (sadly, we currently know much less than half of the tinker-toy pieces that Nature uses) in the next few years, then we should revisit this problem and find out who the companions of Delta-1 are, as well as its inhibitors and how they interact, before we can be confident that we understand what's going on.]

Oldest American Dies at Age 113

October 31, 2002;

Mary L. Parr, believed to be the oldest person in the US and second-oldest in the world, died Tuesday at a retirement community in St. Petersburg, FL at age 113. For more details on her successor(s), please see Table E in the Centenarian Section of this website.

Ref:

AP, "Mary L. Parr, 113; Said to Be Oldest Resident of U.S.," The Los Angeles Times, p. B17 (October 31, 2002).

Sarcopenia Occurs in Old Nematodes

October 30, 2002; C. elegans wiggle around vigorously until midlife (around [6 - 7] days) after which an ominous decline begins. By old age (around [12 - 18] days), even a needle prod elicits only ineffective twitches. Now scientists at Rutgers State University of New Jersey and the Albert Einstein College of Medicine in New York have verified that it's not the nervous system that goes bad as a function of age; it's the muscle cells themselves. This muscle weakness ( sarcopenia) is related to the muscle fibers that under the electron microscope are normally bundled together neatly but with old age become disorganized. What process obliterates the normal architecture with age has yet to be identified.

Profs. Caleb Finch of USC and Thomas Kirkwood of the University of Newcastle upon Tyne in England warn that adult worms, unlike humans, don't have mitotic cells in adulthood (except for the germ line). Human skeletal muscle can be replenished by so-called "satellite cells" under certain circumstances such as trauma. Therefore, the model of muscle wasting in C. elegans may not be relevant to human aging. But then again it just might, and for C. elegans we have the complete genome and cellular embryonic-lineage or fate map to work with.

Refs:

1. Monica Driscoll, et al., Nature (October 24, 2002).
2, "for Worms, It's a Crisis of Movement in Midlife," The Los Angeles Times, p. A17 (October 26, 2002).
3. "Aging Nematodes Tell How Muscles Deteriorate," The New York Times, p. D3 (October 29, 2002).
4. John Travis, "Outmuscled: Muscles, not Nerve Cells, Fail on Old Worms," Science News, Vol. 162, No. 17, pp. 260-1 (October 26, 2002).

Genetic Profile of Mouse Embryonic and Adult Stem Cells

October 28, 2002; Researchers at Harvard University and Princeton University have identified a cluster of 216 genes that are enriched in all three classes of mouse stem cells (embryonic, neural, and hematopoietic).

Refs.

1. Miguel Ramalho-Santos [1], Soonsang Yoon [2], Yumi Matsuzaki[2], Richard C. Mulligan [2], and Douglas A. Melton [1]*, "'Stemness': Transcriptional Profiling of Embryonic and Adult Stem Cells," Science, Vol. 298, No. 5593, pp. 597-600 (October 18, 2002).

ABSTRACT:

The transcriptional profiles of mouse embryonic, neural, and hematopoietic stem cells were compared to define a genetic program for stem cells. A total of 216 genes are enriched in all three types of stem cells, and several of these genes are clustered in the genome. When compared to differentiated cell types, stem cells express a significantly higher number of genes (represented by expressed sequence tags) whose functions are unknown. Embryonic and neural stem cells have many similarities at the transcriptional level. These results provide a foundation for a more detailed understanding of stem-cell biology.

[1] Department of Molecular and Cellular Biology and Howard Hughes Medical Institute (HHMI), Harvard University, Cambridge, MA 02138, USA.
[2] Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
* To whom correspondence should be addressed. E-mail: dmelton@mcb.harvard.edu.

__________________________________

2. Natalia B. Ivanova, John T. Dimos, Christoph Schaniel, Jason A. Hackney, Kateri A. Moore, and Ihor R. Lemischka*, "A Stem Cell Molecular Signature," Science, Vol. 298, No. 5593, pp. 601-604 (October 18, 2002).

ABSTRACT:

Mechanisms regulating self-renewal and cell fate decisions in mammalian stem cells are poorly understood. We determined global gene expression profiles for mouse and human hematopoietic stem cells and other stages of the hematopoietic hierarchy. Murine and human hematopoietic stem cells share a number of expressed gene products, which define key conserved regulatory pathways in this developmental system. Moreover, in the mouse, a portion of the genetic program of hematopoietic stem cells is shared with embryonic and neural stem cells. This overlapping set of gene products represents a molecular signature of stem cells.

Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
* To whom correspondence should be addressed: E-mail: ilemischka@molbio.princeton.edu.

Anti-Aging Medicine: What if the Rate of Aging Were Slowed?

October 25, 2002;

"I don't want to achieve immortality though my work;
I want to achieve immortality by not dying." - Woody Allen

"The truth is that no treatments have been established to to delay, postpone, stop, or reverse aging."
---- Robert Butler, M.D., Member of the Editorial Board of Focus on Healthy Aging.

The life expectancy of a hypothetical 50-year-old American woman today is 81. If somehow cancer, cardiovascular disease, and diabetes were all simultaneously cured overnight, life expectancy would extend for this woman to just 97 years. On the other hand, if the aging process itself were somehow slowed (equivalent to a caloric restriction dietary regime as has been done in rats from birth resulting in a 40 percent increase) then life expectancy would rise to 113 years.

Refs:

1. "You Can't Turn Back the Hands of Time, But You Can Take Many Proven Steps to Live a Longer, Healthier Life," Focus on Healthy Aging: Maintaining Health and Vitality in Middle Age and Beyond, Vol. 5, No. 11, pp. 1, 6 (November 2002).
2. S. Jay Olshansky, Bruce A. Carnes, and Christine I. Cassel, Science, Vol. 256 (1990).

Stem Cells Used to Target Glioblatomas in Mice

October 15, 2002; As reported in today's issue of the journal Cancer Research, scientists at Cedars Sinai Medical Center in Los Angeles injected the brains of mice engineered to have have brain tumors with neural stem cells genetically modified to contain Interleukin-12 (IL- 12), a tumor-killing immune-derived protein. Thirty percent of the treated mice remained cancer free for the long-term, while all the mice in the control group died very quickly.

Ref.

Peter Landers, "Stem Cells Used to Kill Tumors in Brains of Mice," The Wall Street Journal, pp. A1, D1, 3 (October 15, 2002).

2002 Nobel Prize for Medicine for Work on C. Elegans

October 8, 2002; We are pleased to announce that Professor Sydney Brenner of the Salk Institute in La Jolla, California -- along with two of his colleagues Drs. John E. Sulston of the Sanger Centre in England and H. Robert Horvitz of MIT -- has received the 2002 Nobel Prize in Physiology or Medicine. One Million Dollars will be shared equally among the recipients!

Dr. Brenner, long credited with being the brightest scientist who wasn't a Nobel Laureate, today is no longer able to claim that distinction. Born to an illiterate Lithuanian cobbler in Germiston, South Africa in 1927, Brenner worked with Francis Crick at Cambridge on fundamental DNA/Amino Acid coding for many years and now is working with him again at The Salk. More recently, he has argued persuasively for sequencing the DNA of the Puffer fish ( Fugu rubripes) as a model/surrogate for the human genome, due to its remarkably parsimonious sequence (having comparatively little "junk" DNA compared to mammals).

[ Editor's Note: In my view, Brenner's greatest accomplishment was his exhaustive analysis of the embryogenic Fate Map (or Lineage Map) of the microscopic nematode Caenorhabditis elegans that takes a fertilized egg from a single cell to an adult organism of precisely (1,090 - 131) = 959 cells and shows graphically the complete annotated set of daughter cells in each generation. This is the blueprint for the 3-D architecture of a worm. The 131 deleted cells are the scaffolding that is subsequently removed by apoptosis once the organism is complete, sort of like the webbing in between our fingers and toes that are dissolved to expose five digits during the course of limb formation. (The final number deliberately neglects the germ-line cells [eggs/sperm] which are quite variable from one worm to the next. By the way, another complexifying factor is that this particular worm is hermaphroditic, so the sexual interaction among individuals is opportunistic, depending on environmental conditions.)

Brenner went on to identify the nematode genes involved in the apoptosis of these 131 cells (ced-3, ced-4, and ced-9 [Human counterpart is Bcl-2]), giving us a handle on the gene network or motif for Programmed Cell Death (PCD).

At age 75, Brenner did not rest on his laurels. He is taking nematode genes one-at-a-time and putting them into mice to discover what their function might be. I consider this to be one of the most innovative methodologies in biology today, and I don't know of anyone else who is doing this critical work of going from genotype to phenotype using this approach. Undoubtedly, the outcome of this research will someday shed light on the processes of aging and senescence.]

Refs:

0. Click for www.nobel.se in Sweden.
1. Thomas H. Maugh, II, "'Suicide Cell' Work Earns Trio a Nobel: Biologist at Salk Institute in La Jolla Shares Prize in Medicine/Physiology," The Los Angeles Times, pp. A1, 22 (October 8, 2002).
2. Denise Gellene, "Idun Hopes Nobel Attracts Financing: The San Diego Firm is Optimistic that the Award to Its Founder Will Increase Backing of Its Cell-Death Research. But Isn't a Sure Bet," The Los Angeles Times, pp. C1, 14 (October 8, 2002).
3. Idun Pharmaceuticals, a privately held company is San Diego, was co-founded by Dr. H. Robert Horvitz. The company, by the way, is named for the Norse goddess of Eternal Youth. (Click for more details).
4. "The Nobel in Medicine went to Britons Sydney Brenner and John Sulston and American H. Robert Horvitz for Research on Organ Growth and Cell Death that Has Opened Paths to Combating Cancer and Other Diseases," The Wall Street Journal, p. A1 (October 8, 2002).
5. Lawrence K. Altman, "Three Win Nobel for Work on Suicidal Cells," The New York Times, pp. A1, 23 (October 8, 2002).
6. "Gene Scientists Scoop Nobel Prize," CNN (October 8, 2002).
7. Jean Marx, "Nobels Run the Gamut from Cells to the Cosmos," Science, Vol. 298, No. 5593, p. 526-8 (October 18, 2002).
8. J. Travis, "Nobel Prizes Honor Innovative Approaches," Science News, Vol 162, No. 15, p. 229 (October 12, 2002).
9. Hal Cohen, "In Focus: 2002 Nobel Winners," The Scientist, Vol. 16, No. 21, p. 24 (October 28, 2002). 10. "Nobel Prizes for 2002," Scientific American, Vol. 287, No. 6, p. 37 (December 2002).

Stem-Cell Research Funding for State of California

September 22, 2002; Governor Gray Davis is expected today to sign into law California Senate Bill 253 authored by Sen. Deborah V. Ortiz (D - Sacramento) to create a review process for stem-cell research and pave the way for the State Government to shift some of its biomedical research funds toward this new emerging field. "Stem-cell research is responsible research that could potentially save millions of lives," Davis said in written statement. "I am determined to keep California at the forefront of medical research and scientific innovation."

"Paralyzed actor Christopher Reeve is scheduled to join Davis in a conference call following the bill signing," officials said.

Refs:

1. Gregg Jones, "Bill Boosting Stem-Cell Research To Be Signed," The Los Angeles Times, pp. B1, 6 (September 22, 2002).
2. Aaron Zitner, "White House Criticizes State Stem-Cell Law," The Los Angeles Times, p. B6 (September 24, 2002).
[California is the first state to pass a law supporting stem-cell research. On the other hand, Iowa, Michigan, and South Dakota have already passed legislation to ban embryo research or cloning within their borders. "President Bush believes that all policies, state or Federal, need to respect the 'culture of life,'" said Art Fleischer, speaking for the President. "The President differs with Governor Gray Davis on this."
A University of California Discovery Grant Program administered by Prof. Suzanne Huttner, Associate Vice Provost for Research at UC Berkeley, will solicit Research Proposals from 10,500 California stem-cell scientists soon. The program administers a $24.6 million fund.]
3. CNN Health and Reuters (September 22, 2002).
4. California Healthcare Institute, which represents bioscientists and the biomedical industry..
5. "California's Governor Signed Legislation to Allow Stem-Cell Research in the State on Donated Embryos from Fertility Clinics," Wall Street Journal, p. A1 (September 23, 2002).
[This is a challenge to funding restrictions President Bush imposed on cell lines permitted for such use.]
6. Barbara Feder Ostrov, "Davis Signs Nation's First Stem-Cell Bill: Action Sets Up Conflict with the U.S.," San Jose Mercury News (September 23, 2002).
7. Text of State of California Senate Bill 253 which is scheduled to become law in California on January 1, 2003.
8. "Interview with Christopher Reeve," Larry King Live; CNN-TV, 9:00 PM PDT; Monday, September 23, 2002; TRT= 1 hour).
9. "Interview with Christopher Reeve," ABC-TV, 10:00 PM PDT, Friday, September 20, 2002; TRT = 30 minutes.
10. "Christopher Reeve Documentary,: PBS-TV, 10:00 PM PDT, Wednesday, September 18, 2002; TRT = 1 hour.
11, Christopher Reeve, Nothing Is Impossible: Reflections on a New Life (Random House; ISBN: 0375507787; 2002).

High Rate of Hidden Genetic Abnormalities in Cloned Mice

September 13, 2002; Prof. Rudolf Jaenisch of the MIT Whitehead Institute and Ryuzo Yanagimachi of the University of Hawaii published in this week's Proceedings of The National Academy of Sciences, USA on genetic abnormalities in cloned mice. Apparently, 50 percent of the genes involved in "imprinting" are not correctly expressed. (During the imprinting process, only the copies of a gene contributed by the father are active.) This 50 percent error rate was uncovered using a 10,000-gene-chip microarray analysis.

Several cloning researchers have said that "cloned livestock such as cattle, sheep, and pigs are normal and healthy if only they get past birth." However, Jaenisch believes that genetic abnormalities will be found even in these seemingly normal animals, even if some of these abnormalities are not lethal.

Refs.

1. Reuters, "Genetic Mutations Are Part of Cloning Process, Scientists Find Abnormalities in Engineered Mice Explain High Fatality Rates. Dangers of Human Trials Are Highlighted," The Los Angeles Times, p. A38 (September 13, 2002).
2. David Humpherys * [{dagger}] , Kevin Eggan * [{dagger}] , Hidenori Akutsu [{ddagger}] , Adam Friedman *, Konrad Hochedlinger *, Ryuzo Yanagimachi [{ddagger}] , Eric S. Lander * [{dagger}] , Todd R. Golub * [] , and Rudolf Jaenisch * [{dagger}] ||,
"Abnormal Gene Expression in Cloned Mice Derived from Embryonic Stem Cell and Cumulus Cell Nuclei,"
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.192433399

*Whitehead Institute for Biomedical Research and
[{dagger}] Department of Biology,
Massachusetts Institute of Technology,
9 Cambridge Center,
Cambridge, MA 02142;
[{ddagger}] Department of Anatomy and Reproductive Biology,
John A. Burns School of Medicine,
University of Hawaii,
Honolulu, HI 96822;
[] Department of Pediatric Oncology,
Dana-Farber Cancer Institute,
Boston, MA 02115; and
Department of Pediatrics,
Harvard Medical School,
Boston, MA 02115

Contributed by Eric S. Lander, July 22, 2002

ABSTRACT:

To assess the extent of abnormal gene expression in clones, we assessed global gene expression by microarray analysis on RNA from the placentas and livers of neonatal cloned mice derived by Nuclear Transfer (NT) from both cultured embryonic stem cells and freshly isolated cumulus cells. Direct comparison of gene expression profiles of more than 10,000 genes showed that for both donor cell types [{approx}] 4 percent of the expressed genes in the NT placentas differed dramatically in expression levels from those in controls and that the majority of abnormally-expressed genes were common to both types of clones. Importantly, however, the expression of a smaller set of genes differed between the embryonic stem cell- and cumulus cell-derived clones. The livers of the cloned mice also showed abnormal gene expression, although to a lesser extent, and with a different set of affected genes, than seen in the placentas. Our results demonstrate frequent abnormal gene expression in clones, in which most expression abnormalities appear common to the NT procedure whereas others appear to reflect the particular donor nucleus.

||To whom reprint requests should be addressed. E-mail: jaenisch@wi.mit.edu.

Genetics of Mouse Stem Cells Profiled

September 13, 2002, Cambridge, MA; Click for details.

American Life Expectancy Reaches 76.9 Years

September 13, 2002; Statistics just released from the Centers for Disease Control and Prevention in their annual report for CY 2000 (from the National Center for Health Statistics) reveal that American men born today will live to 74 and American women to nearly 80 years. However, the medical-care racial gap persists and adults are considerably heavier. Obesity is destined to become the Number One epidemiological public-health-care problem, after smoking, for all Americans. On the other hand, for selected teenage demographic groups [e.g., black men 15 - 24], homicide is the Number One cause of death. The major advances in life expectation over the last century (47.3 years in 1900) can be attributed to a sharp reduction in infant mortality (better obstetrical technique with C-sections routinely used for complications of pregnancy), reduction in the rate of fatal bacterial infections due to antibiotic therapy, lower rates of accidents per capita, lower rates of cancer (except for lung cancer), and lower incidence of heart disease. On the other hand, the "low hanging fruit" has already been picked (public sanitation, water, and sewage treatment), and we should not expect to see the same sort of advances in the present century that we witnessed in the last unless we address the "problem of aging" itself.

Refs:

1. CNN (September 13, 2002).
2. Rosie Mestel, "Life Expectancy Hits 76.9 in U.S.; Health Costs Soar," The Los Angeles Times (September 13, 2002).

U.K. Stem Cell Bank Under Development

September 10, 2002; London, UK ( AP) The British Institute for Biological Standards and Control, a publicly-funded group, was awarded a contract to set up and manage the new stem-cell bank. Embryonic stem-cell research is moving into high gear in England.

Refs:

1. "U.K. Advances Stem-Cell Bank," The Wall Street Journal, p. D3 (September 10, 2002).
2. Gautam Naik, "Britain Hopes Stem-Cell Bank Will Aid Treatment of Diseases," The Wall Street Journal, p. D4 (September 12, 2002).

Embryonic vs. Adult Bone-Marrow Stem Cells

September 9, 2002; Washington, D.C. ( AP) As published in the latest issue of Science, Profs. Irving Weissman, M.D. and Amy J. Wagers of Stanford University have uncovered some potentially disappointing news that certain adult bone-marrow stem cells appear to be limited in their capabilities to synthesizing blood-line cells only and not all the cells of the body as had been suspected by other investigators. Other kinds of bone-marrow stem cells like stromal or mesenchymal stem cells may be cabable but were not tested by the Stanford group. Click the image above for the Science Abstract from Stanford Medical School and for more details from CNN.

However, "important new evidence that human stem cells can be implanted and become part of muscle tissue suggests that Muscular Dystrophy may yet become treatable," said Dr. Louis Kunkel of Children's Hospital in Boston.

Refs:

1. Nicholas Wade, "Hopes Raised of Using Stem Cells for Treating Muscular Dystrophy," The New York Times, p. D7 (September 10, 2002).
2. AP, "Stem Cells May Treat Muscular Dystrophy," The Los Angeles Times, p. A10 (September 10, 2002).

Human Adult Stem Cells Aid Recovery Post Heart Attack

September 3, 2002; German Scientists reported in today's issue of the Journal of the American Heart Association entitled, Circulation, that they have retrieved adult stem cells from human bone marrow that were inserted into infarcted (damaged) heart tissue and coronary arteries using a balloon-angioplasty technique .for [2 - 4] minutes [6 - 7] times per patient. This technique succeeds over IV injection, since these cells would be likely to home in on other organs in the body and therefore be wasted.

Ref:

Ron Winslow, "Stem Cells Aid Heart-Attack Recovery," The Wall Street Journal, pp. A1, D3 (September 3, 2002).

Human Anti-Bodies Produced in Cloned Calves

September 1, 2002; Researchers at Hematech of Westport, CT and Sioux Fall, SD and Japan-based Kirin Brewery Company say they used a proprietary cloning technique to produce four calves that express a human chromosome fragment coding for a range of human antibodies. The research was the result of an ongoing joint effort to develop a system for human polyclonal antibody-based therapeutics.

Ref:

Inside Industry, "Human Antibodies Produced in Cloned Calves," Genetic Engineering News, Vol. 22, No. 15, p. 85 (September 1, 2002).

Geron Corp. Announces Telomerase Vaccine for Prostate Cancer

August 28, 2002; David Greenwood, Geron's CFO told the press, "Cancer vaccines are an important development on the horizon, and this immune-system-based treatment (patient inoculation with fragments of the telomerase protein) is another potentially very effective way to interrupt telomerase activity." Geron's stock rose 15 percent (59 cents to $4.44) on the news that Geron had applied for a U.S. patent for this technology.

Ref:

Bloomberg News, "Geron Gains on Cancer Therapy," The Los Angeles Times, p. C2 (August 28, 2002).

Oldest Person in the U.S. Dies at Age 114

August 24, 2002;

Mrs. Adelina Domingues, recently accepted as the oldest living American at 114 years old, has died. We have just learned from her grand-daughter that Mrs. Domingues died on Wednesday, August 21, 2002 at 1:30 PM PDT of congestive heart failure at the San Diego nursing home in Spring Valley, CA where she lived. She was born February 19, 1888 in Brava, Cape Verde Islands (off the coast of West Africa). After her marriage, she moved to Massachusetts in 1907.

Adelina attributed her longevity to her daily regimen of eating vegetables and beans and her life-long abstinence from any form of alcohol or tobacco. But she also thought she lived longer because she "never played cards or went to a beauty parlor," something she was very proud of. She was also an expert seamstress.

Ref:

Tony Perry, "Adelina Domingues, 114; Oldest Person in the U.S.," The Los Angeles Times, p. B20 (August 24, 2002).

PPL Therapeutics Clones Double Knock-Out of Porcine GGTA-1 Gene

August 23, 2002; London, UK (AP); Pigs normally synthesize alpha-1,3 galactose sugar molecules on the surface of every cell of every tissue of every organ in their bodies. Unfortunately, this is a signature trigger for the human immune system to commence a massive rejection of any foreign tissue xenograph of a porcine organ, which might otherwise be just the right size, shape, and functionality to replace a defective human organ. PPL Therapeutics, PLC of Blacksburg, VA had succeeded in knocking out one of the two copies of the GGTA-1 gene that makes this sugar but not both. Now they've knocked out both in four different pigs, born on July 25th. Interestingly, about 70 percent of the "knockout" work was funded by the Federal Government. Human clinical studies could begin from two to four years from now. [ Editor's Note: There may be other so-far unknown characteristics of porcine surface antigens that are specific for pigs and not humans that may trigger a more smoldering human killer T-cell immune rejection. This is obviously a stepping stone until we get this foreign-antigen rejection problem nailed down.]

Refs:

1. Gautam Naik, Cloned Piglets May Aid Organ Hunt: PPL Therapeutics Makes Gain in Effort to Improve Transplants' Success Rate," The Wall Street Journal, pp. A1, 8 (August 23, 2002).
2. AP, "Pigs Stripped of Rejection Gene: Cloning Project Seeks to Make Animal Organ Transplants Viable for Humans," The Los Angeles Times, p. A12 (August 23, 2002).
3. Emma Ross, "Cloning Case Seen as Step for Pig Organs in Humans," The Denver Post, pp. 1A, 7A (August 23, 2002).

TIGR To Open Diagnostic Center to Decode Human DNA

August 14, 2002; Dr. J. Craig Venter, former CEO of Celera Genomics, unveiled plans today to open a diagnostic research center associated with The Institute for Genomic Research (TIGR) in Rockville, MD that will be able to decode a person's DNA in seconds for a cost of about $1,000. This process now takes months and costs millions of dollars. Making such a test widely available could help physicians predict what diseases a patient may face and treat medical problems before they arise.

Ref.:

Lanham, MD ( AP) "Scientist Plans Lab to Map Genes Swiftly and Inexpensively," The Los Angeles Times, p. A13 (August 16, 2002).

Critics Lament the State of US Stem-Cell Research, But Japanese Make Progress

August 9, 2002; A study done by researchers at three Japanese universities (Kansai Medical in Osaka, Kurume School of Medicine, and Jichi Medical School in Tochigi) have published in the current issue of The Lancet that implanting autologous stem cells in the damaged limbs of patients with vascular disease can trigger angiogenesis. In the main study, 16 of the 20 patients no longer experienced pain while sitting down. X-rays before and after the stem-cell implantation showed increased blood-vessel networks in 27 of 45 recipients.

On the other hand in the US, even one year after President Bush's decision to make more than 60 different Stem-Cells Lines from around the world available to clinical researchers through NIH, very little actual progress has been made.

Refs:

1. AP, "Stem Cell Implants Boost Circulation, Study Finds," The Los Angeles Times, p. A4 (August 9, 2002).
2. Elizabeth Cohen, CNN Medical Unit, CNN (TRT = 2.5 min.; 2:45 PM PDT Friday, August 9, 2002).

Stem Cells and Macular Degeneration

August 6, 2002; As will be reported in by a team from Scripps Institute in La Jolla, California in the September issue of Nature Medicine, adult bone-marrow cells can stimulate the formation of blood vessels in the retina of mice with an induced disease that mimics the "wet form" of age-related macular degeneration. In related work at the University of Florida in Gainsville, reported in the June issue of Nature Medicine, stem cells appear to migrate to the site of injury in induced diabetic retinopathy.

Ref:

N. Seppa, "Retina Rescue: Adult Stem Cells Form Blood Vessels," Science News, Vol. 162, No. 5, pp. 69-70 (August 3, 2002).

Mouse Genome Now Free on the Internet

August 4, 2002; Los Angeles, CA (CNN/AP) -- An international team has completed the most comprehensive map ever of the genetic code of the mouse, an accomplishment that will make this laboratory animal more useful to scientists studying human health and disease.

Details appear Monday in the On-line Edition of the journal Nature. The map is available for public review on the Internet...

Direct link to Nature..

Nature AOP, published On-line August 4, 2002; doi10.1038/nature00957

A Physical Map of the Mouse Genome

ABSTRACT:

A physical map of a genome is an essential guide for navigation, allowing the location of any gene or other landmark in the chromosomal DNA. We have constructed a physical map of the mouse genome that contains 296 contigs of overlapping bacterial clones and 16,992 unique markers. The mouse contigs were aligned to the human genome sequence on the basis of 51,486 homology matches, thus enabling use of the conserved synteny (correspondence between chromosome blocks) of the two genomes to accelerate construction of the mouse map. The map provides a framework for assembly of whole-genome shotgun sequence data, and a tile path of clones for generation of the reference sequence. Definition of the human mouse alignment at this level of resolution enables identification of a mouse clone that corresponds to almost any position in the human genome. The human sequence may be used to facilitate construction of other mammalian genome maps using the same strategy.
_________________________________________________________________

Refs:

1. CNN.
2. "Map of the Mouse Genome," The Wall Street Journal, p. A1 (August 5, 2002).

Caloric Restriction May Work for Humans

August 2, 2002; In today's issue of Science, Dr. George Roth and colleagues of the NIA, published the result that CR may help people, not just rodents and monkeys. See CNN for more details.

George S. Roth, Mark A. Lane, Donald K. Ingram, Julie A. Mattison, Dariush Elahi, Jordan D. Tobin, Denis Muller, and E. Jeffrey Metter, "Biomarkers of Caloric Restriction May Predict Longevity in Humans," Science, Vol 297, No. 5582 (August 2, 2002).

National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.

From the first paragraph...

"The most robust intervention for slowing aging and maintaining health and function in animals is dietary caloric restriction (CR) Although most studies of this phenomenon have been conducted in rodents and lower animals, data accumulating from rhesus monkeys suggest that CR may also be relevant for primates, including humans. These findings include CR-induced attenuation of age changes in plasma triglycerides and melatonin as well as oxidative damage and glucose tolerance. Current mortality data from our ongoing studies in rhesus monkeys, although not yet statistically significant, reveal that mortality in CR monkeys is about half of that observed in controls (15 percent compared with 24 percent, respectively)"

Embryonic and Other Types of Stem Cells Show Great Promise

July 31, 2002; Discoveries regarding Embryonic Stem Cells (ESC) have kindled excitement about the possibility of using an array of cells to rebuild damaged nerve tissue in a variety of neurodegenerative disease, including Parkinson's Disease, Huntington's Disease, Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Spinal Cord Injury, and Alzheimer's Disease (AD).

Ref:

Constance Holden, "Versatile Cells Against Intractable Diseases," Science, Vol. 297, No. 5581, pp. 500-2 (July 26, 2002).

Optimism May Mean Longer Life

July 29, 2002; According to the August issue of the Journal of Personality and Social Psychology published by the American Psychological Association, the Ohio Longitudinal Study of Aging and Retirement, researchers studied 660 residents of a small town in Ohio and found that those with positive attitudes lived 7 1/2 years longer than those with negative views (22.6 vs. 15 years, respectively). 338 men and 322 women ages [50 - 94] were recruited back in 1975. The study conducted by Yale University researchers was funded by the National Institute on Aging.

Refs:

1. Janee Allen, "A Positive Outlook on Aging May Mean a Longer Life," The Los Angeles Times, p. S3 (July 29, 2002).
2. CNN (July 29, 2002).
3. B. Bower, "Staying Alive with Attitude: Beliefs about Aging Sway Seniors' Survival," Science News, Vol. 162, No. 4, p. 53 (July 27, 2002).

UCSD Scientists Block Heart Disease in Hamsters Using Gene Therapy

July 22, 2002; According to today's issue of Nature Medicine, the gene for phospholamban, a regulatory protein that controls Calcium entry into heart muscle, delivered by an AAV (Adenoassociated Virus) Vector penetrated 60 percent of the myocytes in hamsters with heart disease.

Refs:

1. Ron Winslow, "New Gene Therapy Halts Progression of Heart Failure," The Wall Street Journal, pp. A1, B6 (July 22, 2002).
2. S. Milus, "For Failing Hearts: Gene Therapy Stops Decline in Animals," Science News, Vol. 162, No. 4, p. 54 (July 27, 2002).

Generic Human Embryonic Stem Cells Are Not "Self," As Far As the Immune System Is Concerned

July 12, 2002; Human ES Cells do *not* get a free pass form the immune system, contrary to the earlier wishful thinking of some of our colleagues; MHC antigenic proteins help identify these cells as invaders to Natural Killer white-blood cells, while their rate of rejection increases with differentiation. Teratoma cells and "HeLa" cells were used to calibrate the intensity of the immune rejection. It is speculated that a proposal to modify ES Cells so that they would not express MHC proteins might make them more susceptible to infection or more tumorogenic, so that approach might not be the answer either. ES cells derived from autologous nuclear transfer techniques (cloning) might also lead to rejection, since embryonic antigens could still be considered "non-self." However, prior in vitro differentiation and amplification into needed adult cells before being injecting the cells into a donor diagnosed as lacking that type of cell would be more likely to be "immune privileged." .

Refs:

1. Gretchen Vogel, "Stem Cells Not So Stealthy After All," Science, Vol. 297, No. 5579, pp. 175-6 (July 12, 2002).
2. Published online before print July 11, 2002
Cell Biology
Micha Drukker * [1] , Gil Katz * [2] , Achia Urbach [1] , Maya Schuldiner [1] , Gal Markel [2] , Joseph Itskovitz-Eldor [3] , Benjamin Reubinoff [4], Ofer Mandelboim [2, 5], and Nissim Benvenisty [1, 5]
"Characterization of the Expression of MHC Proteins in Human Embryonic Stem Cells,"
Proc. Natl. Acad. Sci. USA
1. Department of Genetics, Silberman Institute of Life Sciences, Hebrew University, 91904 Jerusalem, Israel;
2. The Lautenberg Center for General and Tumor Immunology, Hadassah Medical School, Hebrew University, 91120 Jerusalem, Israel;
3. Department of Obstetrics and Gynecology, Rambam Medical Center, Faculty of Medicine, The Technion, Haifa 31096, Israel; and
4. The Goldyne Savad Institute of Gene Therapy, Hadassah University Hospital, 91120 Jerusalem, Israel
___________________
Communicated by Philip Leder, Harvard Medical School, Boston, MA, May 17, 2002
(received for review March 13, 2002)

ABSTRACT:

Human embryonic stem (ES) cells are pluripotent cells that may be used in transplantation medicine. These cells can be induced to differentiate into cells from the three embryonic germ layers both in vivo and in vitro. To determine whether human ES cells might be rejected after transplantation, we examined cell surface expression of the MHC proteins in these cells. Our results show very low expression levels of MHC class I (MHC-I) proteins on the surface of human ES cells that moderately increase on in vitro or in vivo differentiation. A dramatic induction of MHC-I proteins was observed when the cells were treated with IFN- [{gamma}] but not with IFN- [{alpha}] or -á. However, all three IFNs induced expression of MHC-I proteins in differentiated human ES cells. MHC-II proteins and HLA-G were not expressed on the surface of undifferentiated or differentiated cells. Ligands for natural killer cell receptors were either absent or expressed in very low levels in human ES cells and in their differentiated derivatives. In accordance, natural killer cytotoxic assays demonstrated only limited lysis of both undifferentiated and differentiated cells. To initiate a histocompatibility databank of human ES cells , we have isotyped several of the published ES cell lines for their human leukocyte antigens. In conclusion, our results demonstrate that human ES cells can express high levels of MHC-I proteins and thus may be rejected on transplantation
. ________________________________
*M.D. and G.K. contributed equally to this work.
5. To whom reprint requests should be addressed:
E-mail: nissimb@mail.ls.huji.ac.il; oferman@md2.huji.ac.il

Editorial on Polio Virus Synthesized from Raw Nucleotides

July 12, 2002; Unfortunately, in today's issue of Science, a DoD/DARPA-sponsored experiment to demonstrate the feasibility of synthesizing a human pathogen from raw DNA-sequence data (publicly available on the Internet) has now been published. The methodology does not appear to be technically difficult, involving an equipment-investment on the order of several hundred thousand dollars and only a few months of full-time effort by a single student biochemist. Raw nucleotide sequences can be purchased from commercial-supplier catalogs with a cashier's check and sent by UPS or even standard mail-order to a P.O. Box with complete deniability on the part of the purchaser's agent(s) without an audit trail.

More importantly, the method described is general-purpose and is not restricted to the Polio Virus (Single-Stranded ssRNA = 7.741 KBases), which is one of the few human pathogens for which most of us already have immunity (for example, Salk or Sabin Oral Vaccine in childhood). To ensure that the laboratory-synthesized Polio Virus would be distinguishable from a wild-type virus (which has now been officially eradicated from Europe as well as North America) in case it escaped into the environment during animal testing, the researchers distributed 19 unique markers (point mutations) in the sequence as a sort of "fingerprint." Although these markers weren't expected to alter the pathogenicity of the virus, the synthetic version was, in fact, less toxic since a dose of [1,000 - 10,000] times more viruses were needed to actually kill a mouse. Don't forget that this work was being carried out at a university, not at a CDC- or Fort Detrick, MD-level containment facility. For reference, the Smallpox virus = 185 KBases, and that clearly would take more effort but would still be feasible according to knowledgeable experts.

As Dr. Craig Venter said on CNBC-TV this afternoon [2], "This publication was deliberately provocative and will not rank as a high point in the annals of science." He was quick to point out that publishing a human pathogen's DNA or RNA sequence in a public scientific journal -- as he has done numerous times -- is an entirely different matter, since "that sort of shared knowledge in the public domain can lead to cures not gratuitous insights for bioterrorists."

An organism's sequence really is the "Book of Life" for that creature, isn't it? But most of us already knew that, didn't we? So, we believe that DARPA needs to be justify its biological- research agenda in a more accountable manner.

Therefore, the GRG is compelled to recommend that raw chemical nucleotides {A, G, T, C, U} now be placed on a "US Commerce Department/State Department Munitions/Strong-Cryptography-Algorithms Restricted List" for NO FOREIGN EXPORT without a specific exemption and that domestic purchase of these biologicals to unlicensed buyers be prohibited by law. (Government licensing to universities and pharmaceutical companies should require an initial site visit.) Such restrictions may make it a little more difficult for legitimate scientists to conduct their work, but the protection afforded to our citizens will be worth it in the long run. This is a matter that could be carried out immediately by Executive Order until such time as appropriate legislation can be passed at a more leisurely pace by the US Congress..

Refs:

1. Antonio Regolado, "Researcher Shows How Terrorists Could Create Deadly Virus: The Genetic Sequence of the Smallpox Virus Is Already Available on the Internet," The Wall Street Journal, pp. A1, B1,4 (July 12, 2002)
2. J. Craig Venter, TIGR, CNBC-TV Interview TRT= 10 minutes (7:30 PM EDT; Friday, July 12, 2002)

ABSTRACT:

Full-length poliovirus cDNA was synthesized by assembling oligonucleotides of plus and minus strand polarity. The synthetic Polio Virus cDNA was transcribed by RNA polymerase into viral RNA, which translated and replicated in a cell-free extract resulting in the de novo synthesis of infectious Polio Virus. Experiments in tissue culture using neutralizing antibodies and CD155 receptor-specific antibodies and neuro-virulence tests in CD155 transgenic mice confirmed that the synthetic virus had biochemical and pathogenic characteristics of native Polio Virus. Our results show that it is possible to synthesize an infectious agent by in vitro chemical/biochemical means solely following instructions from a written sequence.

The President's Council on Bioethics Issues Its Report on Human Cloning with Major Internal Disagreements

July 11, 2002; Washington, D.C. ( WSJ) -- Prof. Leon Kass issued an Editorial this morning describing the Preliminary Report of his Commission regarding Human Cloning ( Human Cloning and Human Dignity: An Ethical Inquiry). [Click for Dr. Kass's Commentary.] However, a significant minority (7 out of 17 members) disagreed with the Chairman's Position regarding a Four-Year Ban on all forms of Human Cloning (including Elizabeth H. Blackburn, Daniel W. Foster, Michael S. Gazzaniga, William F. May, Janet D. Rowley, Michael J. Sandel, and James Q. Wilson). Indeed, the Minority Position did not recommend a moratorium at all, but recommended immediate human therapeutic cloning, subject to appropriate controls The Majority Position supporting a ban included Rebecca S. Dresser, Francis Fukuyama, Robert P. George, Mary Ann Glendon, Alfonso G˘mez-Lobo, William B. Hurlbut, Leon R. Kass, Charles Krauthammer, Paul McHugh, and Gilbert C. Meilaender. Obviously, both the Majority and Minority Positions recommended the banning of human reproductive cloning.
[ Editorial Remark: Active discussions during Commission meetings must have been more acrimonious than I thought they might have been, all things considered, and I only wished that I could have been there to participate in the debate.]

Refs:

1. Joe Palca, NPR Radio (~1:30 PM PDT; July 11, 2002).
2. Leon R. Kass, "Stop All Cloning of Humans for Four Years," The Wall Street Journal, p. A16 (July 11, 2002).
3. "Bioethics Panel Suggests a Cloning Moratorium, The Wall Street Journal, p. B6 (July 12, 2002).
4. Aaron Zitner, "Panel Favors Cloning Moratorium But Not Ban," The Los Angeles Times, p. A1, 11 (July 12, 2002).
5. James P. Pinkerton, "Why Not Clone Our Best and Brightest?" The Los Angeles Times, p. ~B15 (July 16, 2002).
["In May, a team of Australian researchers announced that they were within a decade of reviving the Tasmanian Tiger that was hunted to extinction in 1936."
6. American's To Ban Cloning (ABC)
[ABC is a Coalition of Concerned Citizens and US-based Organizations to promote a global, comprehensive ban on all forms of human cloning.]
7. Denise Caruso, "The Moral Minority: We All Lose When We Leave Right and Wrong to a Clique of Ethics Experts," Wired Magazine, Vol. 10, No. 8, pp. 71-2 (August 2002).
8. Stephen S. Hall, "President's Bioethics Council Delivers," Science, Vol. 297, No. 5580), pp. 322-4 (July 19, 2002),
[ Editor's Note: This three-page article, written by Mr. Hall who seems to have interviewed all the Council members, makes one wonder about the ethics of the Ethics Council itself. Prof. Elizabeth H. Blackburn, a respected molecular biologist at the University of California at San Francisco and member of the minority-report group in the Council said, "At no point was the length of the proposed moratorium (four years) publicly discussed. I have no idea where that number came from." Blackburn, Gazzaniga, Rowley, and other Council members left the June session convinced that a narrow majority supported research cloning a stunning outcome certain to shock both the Bush Administration and Capitol Hill. ... The proponents of research cloning had barely a week to savor their triumph. On Friday, June 28th, panel members began to receive draft language of the policy recommendations, and many were shocked to read the recommendation on research cloning. The draft report said that, by a 10:6 majority the Council recommended a four-year moratorium on research cloning. For many members, it was the first indication that the majority position had changed. Rowley, for example, said she was "really caught by surprise." If one were to read Dr. Kass's Editorial in Ref. 2 above and even the complete 200-page preliminary report itself, one would have had no clue as to the level of dissent and acrimony inside the Council itself.]
9. Letter from Ted Peters and Gaymon Bennett, Christian Theologians, The Center for Theology and the Natural Sciences, Berkeley, California, "For Beneficence, Let Cloning for Research Continue," The Scientist, Vol. 16, No. 16, p. 14 (August 19, 2002).

NIH Terminates Woman's HRT Study

July 9, 2002; Washington, D.C. ( CNN) --- In a move that may affect six million women, NIH scientists Tuesday terminated a major study of Hormone Replacement Therapy (HRT) on the risks and benefits of combined Estrogen and Progestin ( PremPro) in healthy postmenopausal women, citing an increased risk of invasive breast cancer, strokes, and blood-clotting abnormalities. The details of the study known as the Women's Health Initiative (WHI) will be published in next week's issue of The Journal of the American Medical Association (JAMA). There were 16,608 healthy women from ages [50 - 79] who were randomly assigned to either Prempro or placebo over 5.2. years. See the CNN Website for more details.

Editorial Remark: We should not allow ourselves to become hysterical over this one study and "throw out the baby with the bath water," so to speak. We need to tease out such issues as "patch" vs. "pill," since we know that the Route-of-Administration is important (first-pass effect through the liver). Also, Prempro is not very "physiologic," since it is a mix of many different natural equine estrogens. Ongoing clinical trials of pure estrogen must be continued for a few more years before we make a more definitive recommendation (in the year 2005). In the mean time, our lives have just gotten a little more complex. Any newly-postmenopausal women who are currently benefitting from HRT in terms of symptomatic relief would probably be advised to see their OB/GYN rather than capriciously stopping their medication(s), since the very slight differences in risk associated with this one study may well be outweighed by individual short-term benefits.

Refs:

1. Gina Kolata, "Study Is Halted Over Rise Seen in Cancer Risk," The New York Times, pp. A1, A17 (July 9,