Finally, a breakthrough in cancer therapy: a transition of genius!

Posted on June 30th, 2009 in General by Robert Miller

When I entered medical school in the early 1960s, treatment for leukemia was beginning to use drugs that inhibited rapidly dividing cells, with the approach we now refer to as chemotherapy.  In time, physicians learned how to dose those drugs, combine them with radiation and begin to better control all types of cancers with some “cures” established by early diagnosis and sometimes very drastic, potentially life-threatening forms of treatment, such as bone marrow transplant. I have often referred to this era as “better living through chemistry.” Despite the enormous progress we have made in understanding the cellular and molecular mechanisms related to cancer development in cells, the strategy for cancer treatment has often been to go out and look for novel compounds that might have a magic bullet for one type of cancer or another. And, while some very useful agents and treatments have been developed with this strategy, it still relies on the objectives and broad treatments of the “better living through chemistry” era, where you expose virtually every cell in the body to the toxins and often make the patient very sick. You might say that we have been patiently waiting for many years for a breakthrough in cancer therapy based on our new understanding of cellular mechanisms of cancer, which will allow us to get away from the “kill all rapidly dividing cells and then hope that the patient survives strategy.”

Finally things have started to change and I see no reason why we won’t see a great acceleration of these new kinds of strategies in the near future. An element of genius has crept into these new cell and molecular tools for cancer therapy and with them, we can visualize the promise of drastically reducing the toxicity that has long been a hallmark of cancer treatment. We are at the early stage of finally entering the new “molecular era” of cancer therapy and we are beginning to close the door on the “better living through chemistry” era of the last half century. In a very remarkable study reported in Nature Biotechnology, but summarized very nicely in the New York Times, a new ingenious method of killing cancer cells was described that promises to revolutionize all future strategies and thinking.  I’ll try to explain it as simply as I can: first, this was an experimental approach using human cancer cells that had been injected into mice, so it’s not yet a human story, but there’s no reason why this strategy can’t be transferred to human cancers in relatively short order. Second, this therapeutic method targets primarily the cancer cells and leaves unperturbed other non-cancerous, normal cells of the body. Third, the targeting of the cancer cells was done through a two stage strategy, one of which included the injection of an RNA interference set of molecules that turned off a protein that cancer cells commonly have, which functions to transport toxic chemicals out of the cell and makes them invulnerable to chemical treatments that might otherwise do them in–that’s part of the genius of cancer cells. Now the problem with injecting RNA sequences into the cell is that you can’t inject them into the blood stream because they are rapidly degraded by endogenous nucleases or enzymes within the blood. So, the Australian group who authored the report used small derivatives of bacteria called “minicells.” Minicells were coated with an antibody that recognized surface proteins on the cancer cells (abundance of receptors for “Epithelial Growth Factor” or EGF). Once the mincells were injected into the mouse, they attached themselves to the cancer cells; the cancer cells immediately responded by engulfing the minicells, but in doing so, they exposed their interiors to whatever chemicals were in the minicells. In this case, the minicells contained  RNA sequences which entered into the cancer cells and eliminated the expression of the toxin pump proteins that normally served to extrude toxins out of the cell. Once this was accomplished, after a delay, a second group of minicells were prepared that had high levels of the cytotoxic drug, doxorubicin, a chemotherapy agent. This cytotoxic drug was delivered at high concentration into the cancer cells, which could no longer pump the toxin out because the pump protein was disabled. In a very short period of time the cancer cells were eliminated from the mice. The untreated mice which served as the controls died within a month of the tumor injections. The human cancers injected into the mice were highly virulent tumors, one of which was a type of colon cancer and the second was a breast cancer explant. They had not metastasized, so it remains to be seen if metastatic tumors can be treated in this same way.

You cannot read the paper or the NYT article without getting excited when thinking about the future of cancer therapy. We have finally crossed the bridge into the molecular arena where no doubt we will find new formidable challenges, but we can foresee a vast new array of clever strategies available to us as we get more sophisticated in targeting tumor cells with ingenious strategies designed for their destruction. You can also appreciate that our new molecular chemotherapy targeting can be achieved without significant downtime for the patient, as so few normal cells will be done in. I don’t foresee that we will one day go to the drug store and get a pill based on the kind of cancer we have, but we are surely turning an important curve on the way to better, more effective therapies.  This new strategy requires some design skills at the molecular and cellular level, but conceivably we will one day soon have a small group of minicells or something similar, each of which will provide a powerful cure to one or more types of cancer. At long last a breakthrough of an ingenious character has surfaced. While I am not a cancer researcher and others more familiar with the field might offer appropriately tempering notes of caution, this is the most exciting paper I have read in many years on new therapeutic strategies and I can see this breakthrough spreading like wildfire throughout the research and cancer treatment community. This result was no lucky accident–it’s design was made possible by the long, difficult struggle to understand how cells work and how to manipulate them successfully to our advantage. You couldn’t get to where we are today without heavy, prolonged research funding. And just think about the possibility of ingenious cures for cancer which may be arriving just in time to cure us all of our cancers so we can die of some grotesque global climate disease–maybe some type of new flesh-eating fungus! How inglorious to die of jungle rot in Minnesota, coming at a time when we finally will have two senators!

RFM

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I, the juror, redux

Posted on June 30th, 2009 in Culture,Politics by Robert Miller

I had my turn as a juror in the Hennepin County judicial system, in downtown Minneapolis, from June 15, 2009 to June 23, 2009. Although I was told that my obligation as a juror would last two weeks, what really happens is that once you serve on a single jury, you are excused from further service. In principal, your jury service could extend way beyond two weeks if you wound up on a jury deliberating an extended case. I was on a jury that deliberated a good part of only one day and came to a not-guilty conclusion on an assault case (one involving a young Somali husband and wife that I  thought should never have been brought into a criminal court). But, my first interview for jury duty came on my second day of service. This was a drug case, where a young black male was being charged with violations of our drug laws, though the exact nature of the charges were not spelled out and would not be available until the jury was impaneled. So, this gave me a chance to follow through with what I talked about in a previous posting. More than two dozen potential jurors were interviewed with the same set of questions in order to arrive at a jury of 12 men and women, with a thirteenth member to serve as an alternate. The alternate gets excused from duty once the jury is sent by the judge into the jury room to deliberate–when the lawyers have finished presenting their cases.

As each juror was questioned by the judge or by each of the two attorneys, it was clear that one of the main objectives was to determine if anyone had a grudge or a bias against the legal system or held suspicions about the neighborhood where the alleged crime took place, or had a negative attitude about the police.  “Were you arrested before?” “Did you go to trial?” “Were you convicted?” “How do you feel about how the legal system handled your case?” “Have you witnessed police engaged in a violent altercation?” One jurist, a young black man was eventually excused from jury duty because he described a friend, a black male, who had been beaten by police for no apparent reason, leaving him with a very negative attitude about police and an entrenched bias that white police officers are racially bigoted.  He was eventually dismissed from jury duty and sent back down into the pool of jurors for possible selection on another jury.  But, given the emphasis that the judges and attorneys place on attitudes about police, I seriously doubt he will ever wind up on a jury, at least not one in Hennepin County (of course, for all we know, that was his cleverly designed strategy for getting out of jury duty and if so, it should work in perpetuity).  Other questions given to all jurors included “do you have a grudge against police?”  “Will you accept testimony from police officer witnesses and regard it the same as that of any other citizen (I had to think about that one)?”  “Do you have relatives or friends that have been arrested?”  “Has that experience impacted on your views about the legal system in Hennepin County?”  The juror interrogation system was initiated by the judge who asked some questions first, usually quite general, like your name, occupation, number of children and their occupations, followed by a general question about whether anyone of the panelists would have trouble accepting directions from the judge to obey that letter of the law in reaching a decision? I was the only one in the group that raised my hand, but the judge did not query me further on that topic.

Because I raised my hand when the judge asked if any jury members might have trouble following her instructions on the law, both the prosecuting and defense attorneys singled me out for additional questioning. When I was asked what objections I might have against following the judge’s instructions, I responded by saying that I could not convict anyone on a drug charge because our drug laws have helped to create a Leviathan in our prison population, a looming social disaster in which we currently have 2.4 million people in prison with sentencing laws so harsh that a first time drug offender can get the same sentence as someone convicted of homicidal manslaughter (7 years in Minnesota: I had studied the drug laws of Minnesota before I went for jury duty). I went on to say that the drug war in our society was a complete social disaster and that international organizations, such as the Prison Studies Center in London, concluded that the American rate of incarceration made the United States a “rogue state” by not following a penal code system that is normal for other Western countries. I pointed out that China, a country we seem to feel is harsh on it citizens (which they are) nevertheless has fewer people in prison (1.6 million) than we do.

You can appreciate that the defense lawyer seemed to be pretty happy with me sitting on the jury, but the prosecuting attorney went further by responding, “Mr. Miller, are you aware that you are being asked to uphold the law when the judge asks you to decide on this case?”  I responded by saying that many major advances in our legal system and our social justice came about when citizens violated laws that they thought were unjust. I added that we would never have had the civil rights laws passed in the 1960s, if we hadn’t violated many laws to point out the social injustices that were being committed against blacks at the time: people were arrested or even killed for their refusal to obey those existing laws. I expressed the view that the situation with our drug laws is, for me and many others,  now similar to the situation we faced in racial America in the 1960s–in fact I emphasized that our drug laws are nothing less than the new form of racism, because they were structured such that poor blacks, who were more often the dealers, got much stiffer drug sentences than whites, who were often the end users, those who typically received much lighter sentences if they went to prison at all. I added that, while we like to think of ourselves as a technically advanced society, one of our fastest growing jobs are those related to prisons, including  prison guards. The prosecuting attorney, a well dressed white woman, looked at me and said “I don’t think you are a suitable juror for this case.” I responded by saying that I probably was not a suitable juror for her side of the case and everyone seemed to chuckle a bit, as the attorney smiled at me. Both attorneys approached the judges bench, at which time fairly loud, white noise was played over the loud speakers so that we couldn’t hear their conversation. A moment or two later the judge told me that I was dismissed from the jury and needed to report back to the jury selection pool. As I left the court room, both attorneys smiled at me as if they approved of my actions.

I reported again to the jury selection room, got sent up for another jury selection process, where my reputation as an opponent of the drug laws followed me. I was asked again by the prosecuting attorney about my views on the drug laws and I more or less repeated the statements I made earlier. I gave some assurance to the attorney that my attitude towards violent crime was very different than my attitude about our drug laws and for some reason, I wound up being selected as a juror for that case, even though all my more experienced friends told me that I would never get picked for jury duty. After one day of deliberation, we found the defendant not guilty of assaulting his wife, primarily because the prosecution didn’t have a strong case–but that’s another story.

During the trial proceedings, I had two jurors, one a real estate agent and the second a retired banker,  come up to me and tell me that my brief polemic against our penal system and our drug laws moved them to think about our criminal justice system for the first time in their lives. I came away with the impression that if judges, jurors, lawyers and other citizens who come through our court system, routinely heard juror citizens complain about the racial bias and unfair application of our laws and the socially destructive nature of our drug laws, that a powerful message would begin to resonate within our communities about the inequities and harsh sentences we give to those convicted of crimes. Our policy of “zero tolerance” has become a policy of “zero intolerance.” In actuality, I think that judges and lawyers also believe that our drug laws are hopelessly biased and unfair and that the war on drugs is a social disaster, but they can only enforce the laws not change them. Let’s face it, when did you hear any politician running for office based on a platform of reforming our penal code or reducing our prison population. Americans are deathly afraid of having any Guantanamo prisoners on American soil, even if it is known that they are completely innocent of any terrorist acts,  and, by the same token, Americans are afraid to have anyone convicted of a crime living in their neighborhoods. We can only resolve these problems by providing these impoverished neighborhoods with decent job prospects and opportunities for educational experiences, like the program articulated  by Van Jones in his Green Collar Economy book.   You have to start somewhere. I hope that if or when you get called to jury duty, you express your outrage about America’s pathological incarceration rates to your fellow jurors and those in the legal system, as one way of protesting against another unique brand of American injustice. When America commits racial or social injustice, we tend to do it in a big way. The American Indians, Black slavery, the invasion of Iraq and the social pathology of our legal system, define part of the American character for solving problems by having people disappear. But we have run out of land, we destroyed Iraq and we continue to wage war on our poorer neighborhoods, aided by a prison system that virtually makes it illegal to be poor and uneducated in America. I think Neanderthals could have done better.

I believe there is a deep flaw in the American character, but it is not a flaw per se in Americans, rather a flaw in the political forces that prey on American fears and make them coalesce into a single set of harsh attitudes about how to manage the things they fear the most, including crime and the use of drugs. You can see this unrealistic fear today in the attitudes of many Americans towards undocumented immigrants. What politican would dare stand up and announce that passing NAFTA (North American Free Trade Agreement) allowed U.S. subsidized corn to enter into Mexico, displacing many Mexican farmers who couldn’t compete with our subsidized corn, who then migrated into the U.S. to try and find work and send money back home? These  harsh American  attitudes are brought together through the lens of politics, which currently represents the only method we have for creating our political solutions. But, right now we are at least on the verge of seeing a new force for social change bypass the political option and, through communication devices such as the internet, begin to interconnect a group of people who want solutions that work, not just solutions that make people disappear. We are beginning to think seriously about health care and climate change and perhaps down the road we can begin to think about reducing our prison population by providing better jobs and education opportunities for all Americans and find a way to pay for all this by reducing our military expenditures. Have you noticed that the Pentagon has yet to take a hit on any budget reduction policy?

RFM

Crossing the moat into Dover

Posted on June 27th, 2009 in Culture,Politics,Religion,Science by Robert Miller

This is the tenth anniversary of the Dover school board decision in which “intelligent design” had its day in court and came up short. In celebration of this anniversary, I am reissuing “Crossing the moat into Dover.” This trial was all about converting creationism to intelligent design. The reason you have not heard much about either lately can be traced to the outcome of the Dover school board decision.

A biological scientist in America has always felt a little uneasy about the surrounding culture  in which he or she lives and in the past two decades or so, this sense of  being ill-at-ease with the outside culture of America has only become more intense. The rising crescendo of religion has a lot to do with it. One has only to drive a few miles outside of the metropolitan area in which  I live to see an abundance of anti-abortion billboards and other religious symbolism, speaking to a different culture, but an ever present reminder that the cultural wars are alive and well in Minnesota.

A large sector of the research biologists in this country work in universities and feel comfortably isolated from the outside world, by the friendly surrounds provided by students and colleagues who share a common set of interests and commitments, though not necessarily a common political and social identity. But, it’s good enough for government work. Most research university campuses have a decidedly blue color to their political slant, if for no other reason than their support is very dependent on the Federal government. For the students, the coloration is often not quite so clear, though it seems to be shifting towards the blue end of the visible spectrum.  Expanding knowledge is a serious commitment for the research university  and has been hugely beneficial to American industry, public health and social progress. But the university environment is in many ways an odd place, something like an ancient castle, surrounded by a virtual moat to protect those within, well separated from those that are hostile to its purpose and mission. Sometimes I wonder if we don’t feel a little like the Irish monks must have felt in the medieval monasteries when they were the sole scribes of knowledge and scholarship, isolated from a more hostile and ignorant world, with their monasteries often perched on islands for their protection and life-long sanctuary.  While it is not always apparent, the attitude inside the castle of today is that of a serious learning environment on a crash program and a deep thirst for new knowledge,  with the campus insulated by the  virtual moat which protects the interior from the most culturally destructive forces in the country.

The crazies in America, on the outside of the moat looking in, include the religious fundamentalists, the born-again Christians, the right wing fringe groups, the skinheads, survivalists, neonazis and other white nationalists to name just a few.  Individuals from any of these groups may cross the moat and enter the castle, but thus far, the larger movements supported by these groups have not penetrated with sufficient force to change the mission, not nearly as much as they would like. But the university inside is not self-sufficient. Our research can only proceed with Federal support and already, in the case of stem cells or particle physics, these outside forces have helped to diminish the image of America as home to  the greatest centers  for science in the history of Homo sapiens. That image is fading rapidly, perhaps even gone for those living outside of America.

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