The Rest of the Story

This is a roundup of news pertaining to cloning and stem cell research. The first item is good news for those who advocate use of adult stem cells.  The second item is bad news for those who oppose the use of embryonic stem cells.  The third article is about therapeutic vs. reproductive cloning.  It illustrates how counterproductive it is for the current Administration to spurn the United Nations. 

New way to convert adult human stem cells to dopamine neurons
Posted on Monday, October 25, 2004 @ 3:30 PM PDT by bjs (Science Blog)

Researchers at Jefferson Medical College have found a new way to coax bone marrow stem cells into becoming dopamine-producing neurons. If the method proves reliable, the work may ultimately lead to new therapies for neurological diseases such as Parkinson's disease, which is marked by a loss of dopamine-making cells in the brain.

Developmental biologist Lorraine Iacovitti, Ph.D., associate director of the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia and her co-workers had previously shown that by using a potion of growth factors and other nutrients in the laboratory, they were able to convert adult human bone marrow stem cells into adult brain cells. [...]

While nearly all cells looked like neurons with axonal processes, they invariably reverted back to their original undifferentiated state in two to three days.

Dr. Iacovitti and her co-workers instead attempted to grow the cells in a different way. Rather than an attached monolayer of skin-like cells, they grew the bone marrow cells in suspension as neurospheres -- groups of cells early in development -- akin to the way neural stem cells are grown.

They found that the newly differentiated cells didn't merely look like dopamine neurons, but expressed traits of neurons and related cells called astrocytes and oligodendrocytes -- cells derived from neural stem cells. What's more, the neurons produced tyrosine hydroxylase, an enzyme needed to make dopamine.

She reports her team's findings October 25, 2004 at the annual meeting of the Society for Neuroscience in San Diego.

The Jefferson scientists also found a second enzyme involved in dopamine production, and an important molecule called the dopamine transporter.

Those opposed to the use of embryonic stem cells (ESC) often argue that adult stem cells (ASC) offer a greater promise for therapeutic applications. At first, this perplexed me. After all, if the argument against use of ESC is based upon the notion that all embryos are human, and destruction of such embryos is absolutely forbidden, then the relative merits of the two cell types should not matter. However, I have learned that, for some people, it does matter. Some persons might argue that use of ESC is OK, if they can produce benefits that are not available by any other means. This argument might provide exceptions to the absolute ban on use of ESC. If it can be shown that all the same benefits can be derived from ASC, then there would be no exceptions that would permit use of ESC.

For some people, the finding of conclusive evidence for a therapeutic benefit from ASC might be seen as strengthening the argument that there is no justification for use of ESC. This is not really a valid line of reasoning, of course, since the potential benefits of ESC cannot be known unless research on ESC is permitted.

The second article is bad news for opponents of ESC research:

Stem cells home in on brain cancer
Jim Giles (Nature News)
Arming embryonic stem cells with anti-cancer agent could help create new therapies.
Published online: 25 October 2004; | doi:10.1038/news041025-6

Human embryonic stem cells could be used to seek out and destroy a fatal form of brain cancer, according to US researchers.

Experiments in mice with brain tumours show that the cells will migrate across the brain and deliver an anticancer payload. Human clinical trials could begin in two years' time, the researchers said on 24 October at the annual meeting of the Society for Neuroscience, held in San Diego.

Biologist Evan Snyder modified stem cells taken from a human embryo, adding a gene that made the cells express a tried and trusted antitumour molecule known as TRAIL. When injected into mice with brain tumours, the cells homed in on the cancer and pumped out enough TRAIL to cut the tumour size by an average of 50%, and up to 70% in some cases.

The cells are thought to track the tumour by following chemical signals emitted by the immune system molecules that attack, but ultimately fail to destroy, the cancer. Snyder, who is based at the Burnham Institute in La Jolla, California, says similar behaviour has been observed in other animal models of brain injury, where naturally occurring stem cells will travel towards and attempt to repair damaged areas. [...]

Snyder adds that the work is an important proof of principle and that TRAIL is not necessarily the best way of attacking cancer. Stem cells could be modified to express other anticancer molecules, or a combination of cells, each equipped with different molecules, could be used in concert.

Naturally, in order for any such therapy to work, it is essential that the patient's immune system not attack the therapeutic cells. In this particular application, it also is essential that the cells be able to migrate to the desired location. So far, ESC are the only cells that have been shown to act in this way.

Switching topics, the next article pertains to human cloning research:

UN delays cloning vote
US speaks out in support of total cloning ban, vote may take place soon
By Alison McCook (www.the-sceintist.com)
October 25, 2004

UNITED NATIONS—The legal committee of the UN's General Assembly concluded the year's second day of debating whether to ban human cloning on Friday (October 22) without taking a vote, leaving the issue to percolate further in the minds of the deeply divided—and still undecided—member states.

On Friday, Susan Moore, the US Special Advisor, addressed the committee and reiterated the country's position in favor of the total cloning ban. Therapeutic cloning turns "nascent human life into a resource or commodity to be mined and exploited, eroding the sense of worth and dignity of the individual," she said. "For this reason, a partial ban that prohibits reproductive cloning but permits therapeutic, research, or experimental cloning is unacceptable to the United States and many other countries."

The UN has been trying to reach agreement on a convention for more than 2 years. On Thursday (October 21), UN Secretary General Kofi Annan announced that he supports the use of cloning in therapeutic research, opposing the United States and more than 60 other member states that currently support a resolution proposed by Costa Rica that would ban all forms of cloning.

Some 20-odd member states have said they support a separate resolution, put forth by Belgium, which recommends a ban on human reproductive cloning and leaves the decision about therapeutic cloning up to individual states. Under this proposal, members have the option of a total ban, a moratorium on therapeutic cloning, or regulated use of the practice under legislative controls. [...]

Bernard Siegel, executive director of the Genetics Policy Institute, an organization that opposes reproductive but supports therapeutic cloning, told The Scientist he was pleased no vote was taken, given that in previous years, a majority of delegates appeared to support a total cloning ban. The longer the committee waits to vote, the more time scientists have to prove the potential of therapeutic cloning, he said. "Time gives an opportunity to educate."

Moreover, Siegel said he believed that opinion was slowly shifting away from a total cloning ban. For instance, some African nations that previously appeared to support the total ban now appear to have changed their minds. "There's an erosion of support [for the total ban]," Siegel said.

Siegel said he believed some UN member states were closely watching the results of the upcoming US election, given that the US has a strong influence, and President George W. Bush's opponent, John Kerry, supports therapeutic cloning. "If Kerry wins, they will feel less inclined to vote the way of the Bush administration," he said.

The failure of the USA to get a vote on the subject is something that may have been inevitable. However, given the disdain we have shown the UN in recent years, it is possible that our weakened position there has lessened our influence, making it less likely that we would be able to bring the matter to a vote. This, I think, demonstrates the folly of our recent move toward unilateralism. Of course, Mr. Siegel is not the only expert on the subject. But regardless of the specifics of this particular issue, the point still stands, that the best way for the Bush administration to press for pro-life issues is to enlist the cooperation of the International community.

UPDATE: On 10/27/04, an article appeared on the BBC site, reporting on a case of a person whose eyesight was restored after a transplant of retinal cells taken from an aborted fetus:

US scientists have successfully restored a woman's vision using eye cells taken from aborted foetuses. But while hailing their results as a triumph, the University of Louisville researchers are worried critics will say they are promoting abortion. The UK has clear guidelines to ensure people cannot conceive and terminate a baby to treat another person, but similar rules do not exist in the US.

Again, the USA is falling behind the rest of the world, as legislation is not keeping up with scientific advances.

American Blog Party  and Brad DeLong have links that point to a PIPA poll, presumably to promote progressive public policy.  The poll shows what proportion of people hold certain beliefs about current geopolitical topics.  They also compare the frequency of these beliefs among Bush supporters compared to Kerry supporters.

Even after the final report of Charles Duelfer to Congress saying that Iraq did not have a significant WMD program, 72% of Bush supporters continue to believe that Iraq had actual WMD (47%) or a major program for developing them (25%). Fifty-six percent assume that most experts believe Iraq had actual WMD and 57% also assume, incorrectly, that Duelfer concluded Iraq had at least a major WMD program. Kerry supporters hold opposite beliefs on all these points.

Similarly, 75% of Bush supporters continue to believe that Iraq was providing substantial support to al Qaeda, and 63% believe that clear evidence of this support has been found. Sixty percent of Bush supporters assume that this is also the conclusion of most experts, and 55% assume, incorrectly, that this was the conclusion of the 9/11 Commission. Here again, large majorities of Kerry supporters have exactly opposite perceptions. [...]

Propaganda?

When my wife was in college, she wrote a paper on the rationing system that was used in the United States of America during World War II.  In researching this assignment, she spoke with a number of people who were alive during the War, such as her maternal grandmother.  At one point, asking about an unrelated topic, she asked her grandmother what she thought of the propaganda that the US used during the War.  Her grandmother was offended, averring that our  government would do no such thing.

When my father went to Japan, in 1946, he was nervous.  The reason he was nervous is that the formal Occupation was just getting started, and he had been told what heartless, amoral beasts the Japanese people were.  Since he was one of the few soldiers who could speak Japanese, he got the job of going door to door, interviewing people, so that the Occupation would know who was where.  He was supposed to ask them if they had any weapons, etc.  In actuality, though, he found the people to be courteous, polite, and accommodating.  Usually he would sit down with the citizens over a cup of tea.  He had many conversations about traditional Japanese silk painting, bonsai, language, and other matters of culture.  Basically, he found out that the US government had been lying to its citizens about the nature of the enemy. 

He still grows his own bonsai in his back yard.

Not all propaganda is terrible.  For example, the US Army sponsored  a repeat broadcast of the show, Band of Brothers, on the History Channel. 

‘Band of Brothers’ series features six Soldiers
By Kara Motosicky
March 29, 2004

WASHINGTON (Army News Service, March 29, 2004) –The personal experiences of six Soldiers will be highlighted as part of the airing of the “Band of Brothers” mini-series on the History Channel.

The segments connect the Soldiers fighting for their country today to the men who fought with Easy Company during World War II.

The Soldiers’ stories began airing last week as promotional segments for the mini-series, which is based on the best-selling book by Stephen Ambrose that features the Soldiers of “Easy Company.”

The promotional segments will vary in length from one to 10 minutes. A half-hour preview program, now showing on the channel, caps the segments. The Soldiers will give lead-ins and recaps of most episodes in the series.

The program ties together the historical and modern Army by tracing a lasting set of values. The footage features Soldiers who have recently returned from Iraq and Afghanistan talking about their experiences serving overseas and what their Army service means to them. Their stories are paralleled with those of the men of Company E, 506th Parachute Infantry Regiment, 101st Airborne Division.

This interweaving of modern soldier's stories with the semi-historical film is a mild form of propaganda.  I don't object to that.  But what can we make of the fact that a majority of Bush supporters believe things about the Iraq war that are just plain false?  Was some kind of propaganda used to promote these mistaken beliefs? 

From Rense.com:

"Simply stated, there is no doubt that Saddam Hussein now has weapons of mass destruction."
- Dick Cheney, August 26 2002

Stated that the Iraqis were "providing bomb-making expertise and advice to the Al Qaeda organization."
- Cheney in September 2003.
 
"Right now, Iraq is expanding and improving facilities that were used for the production of biological weapons."
- George W. Bush, September 12 2002

 "Our intelligence officials estimate that Saddam Hussein had the materials to produce as much as 500 tons of sarin, mustard and VX nerve agent."
- George W. Bush, State of the Union address, January 28 2003

"If he declares he has none, then we will know that Saddam Hussein is once again misleading the world."
- Ari Fleischer, December 2 2002
 
"We know for a fact that there are weapons there."
- Ari Fleischer, January 9 2003

from WaPo:
"I think the burden [of proof] is on those people who think he didn't have weapons of mass destruction to tell the world where they are."
Fleischer, on July 9 [2003].
 
[...ad nauseum]

What is the difference between propaganda and ordinary lying?  Propaganda is systematic, premeditated, and carried out over a wide scale in order to sway the beliefs of a large number of people.  Now the PIPA study shows that it has worked.

The-Scientist has a nice roundup of developments in pharmaceuticals for neurological and psychiatric conditions.  There is one that they do not mention, though: RU-486. Since I always like to add something to news or science articles I find on the 'net, I provide a little bit of information about that.

Volume 18 | Issue 20 | 48 | Oct. 25, 2004
The Ailing Brain: A Pressing Need for New Treatments
Research in Alzheimer disease abounds, but the pipeline also looks promising for other neurological and psychiatric conditions
By Karen Pallarito

Neuroscience has made impressive strides since 1936 Nobel laureates Henry Hallett Dale and Otto Loewi first showed that chemicals transmit signals between nerve cells. Yet decades later, scientists have only begun to tap potential therapeutic treatments that target brain and nervous system disorders.

Enormous demand exists for medicines, vaccines, and devices that not only alleviate neurological or psychiatric symptoms, as many current treatments do, but also stem the progression of these debilitating conditions. Statistics from the World Health Organization underscore the unmet need: As many as 50 million people worldwide have epilepsy, 37 million live with dementia, 5.5 million die each year of stroke, and 121 million have depression. Demand will likely grow as the population ages, people live longer, and treatments for these conditions improve.

The current market for neurological and psychiatric treatments, at roughly $80 billion for the Group of Seven industrialized nations, could climb to $120 billion in five to 10 years, predicts Kate Hohenberg, therapeutic area director at Decision Resources, a Waltham, Mass.-based pharmaceutical research and advisory firm. The projected figure reflects growth of some existing drugs and the introduction of new therapies. Analysts anticipate some impressive winners, even blockbusters, among today's experimental treatments.

The article includes a review of some of the recently-marketed products, and some that may come to the market soon. These include Neurochem's Alzhemed, a drug that seeks to prevent the sticky build-up of beta-amyloid plaque in the brain. The amyloid plaque is one of the pathological features of Alzheimer disease. The drug is entering Phase III trials, the last phase before a drug is approved. They also mention Prana Biotechnology's Clioquinol. That is a drug that binds to copper and zinc; this effect slows the development of plaques. What is interesting here is the history of the drug:

Clioquinol, first introduced decades ago as a diarrhea medication, caused nerve damage and blindness in thousands of people, particularly Japanese; the oral form of the drug eventually was pulled from the market.

That does not look promising. But there are two factors to consider. First, we now have a much better understanding of pathophysiology. and genomic medicine. As a result, we are in a much better position to deal with whatever toxicity the drug may have. Second, the risk presented by a drug must be understood in the context of the condition one is trying to treat. Risks that are plainly unacceptable for treatment of diarrhea may be acceptable for treatment of Alzheimer disease.

The article goes on to mention some upcoming products for treatment of depression, neuropathic pain, insomnia, Parkinson disease, stoke, and multiple sclerosis.  One drug that is promising, but which was not mentioned in the article, is mifepristone, also known as RU-486. 

Mifepristone has been used to treat Cushing disease, induce abortions, and as an emergency contraceptive.  It currently is in Phase II trials  for treatment of bipolar depression.  An earlier study  at Stanford indicated that the drug can be used to treat psychotic depression.  Subsequent studies (1  2)  have offered some degree of confirmation of effectiveness. 

It may seem counterintuitive that an abortion pill could treat severe depression.  However, there is a good theoretical foundation for this dual effect:

Originally mifepristone was developed as a steroid treatment for Cushing's disease, to block the adrenal hormone cortisol.  But since progesterone receptors and cortisol receptors are structurally related, mifepristone also blocks progesterone, an effect that makes it useful as an abortifacient and, in smaller doses, as an emergency contraceptive.

Research over the last 17 years has revealed that cortisol, a hormone released during times of significant stress, is extremely elevated in psychotically depressed patients.  It seems their sustained levels of cortisol create a chronic stress reaction.  This in turn may cause psychotic depression, including memory problems, sleep disturbances and hallucinations.

Blocking glucocorticoid receptors is a serious business.  It is unlikely that such a treatment could be used for chronic maintenance treatment of depression.  However, psychotic depression is imminently life-threatening, so a higher risk may be appropriate.  

Traditionally, patients with psychotic depression receive one of two treatments:  combined antidepressant and antipsychotic medication, or electroconvulsive therapy (ECT).  Even when effective, both treatments are relatively slow and can leave symptoms that last for months.

"With mifepristone (RU-486) there's a very quick intervention.  The patients often feel better and then we can put them on conventional antidepressants without the antipsychotics or ECT," Schatzberg says.  "What's interesting is that the results are not effervescent.  The patients feel better and it lasts.  Nobody's had to come back, nobody's had to undergo ECT."

[presumably, Dr. Schatzberg actually said "evanescent," not "effervescent."]

It will be years before we know if mifepristone has any clinical utility.  Even if it does not pan out, it is possible that research of other glucocorticoid receptor modulators could lead to something useful.  If it does turn out to be a valuable drug, it will be interesting to see what the political response is, when it is introduced for its new purpose.