The PhD: Value and Use

Nature has a small piece on the growth of PhDs and their alleged mis-direction. My observations are based upon 50 years of doctoral/post-doctoral involvement with time spent in and out of academia.

What is a PhD good for? Perhaps a good question. It takes time, money, dedication, delayed gratification. It produces a highly trained and filtered individual. It is an individual who has intellectually achieved as well as having demonstrated an ability to dedicate great resources with limited returns for a longer term benefit. What is the benefit? The ability to see and produce what the less well trained individual does, perhaps. It should not be a training ground for Lab Tech replacements, low cost, well trained worker bees who when they are burned out are replaced by new worker bees, an endless supply.

In Germany many PhDs go into industry. There must be more Doctors of some specialty in Germany per sq km than any other species. I think I even seen some Dr so and so at the Munich ticket counter service passengers. So the education per se is not the issue. The issue is; how is it used.

The Nature article states:  

The numbers show newly minted PhD students flooding out of the academic pipeline. In 2003, 21,343 science graduate students in the United States received a doctorate. By 2013, this had increased by almost 41% — and the life sciences showed the greatest growth. That trend is mirrored elsewhere. According to a 2014 report looking at the 34 countries that make up the Organisation for Economic Co-operation and Development, the proportion of people who leave tertiary education with a doctorate has doubled from 0.8% to 1.6% over the past 17 years.

So in the US we are producing them at a great rate. But they can and should find places in industry. The Academy does not need them, cannot use them, other than as cheap labor, and their use is maximized monetizing those skills, not trying to hang on. They should be aware of that from the get go. Back in the 60sw at MIT I knew of few of my classmates finishing PhDs trying to find teaching spots. They wanted jobs, and for a while there were a few, then Nixon collapsed the country in 1971, and none were around. At least we could become electricians!

Now here Nature states the crux:

One reason is that there is little institutional incentive to turn them away. Faculty members rely on cheap PhD students and postdocs because they are trying to get the most science out of stretched grants. Universities, in turn, know that PhD students help faculty members to produce the world-class research on which their reputations rest. “The biomedical research system is structured around a large workforce of graduate students and postdocs,” says Michael Teitelbaum, a labour economist at Harvard Law School in Cambridge, Massachusetts. “Many find it awkward to talk about change.”

 Yes, cheap labor, in hope of some dream. In fact they would be better off in industry, and industry would be better for using them and the assets they bring. All too often industry, especially MBA type managers, view PhDs as "head in the cloud types" or "single focus" types. In reality the PhD can do more than any MBA, they can create value not just transfer or worse destroy value. The PhD should be viewed as a peer, one who can add as much value to an establishment as any other and at times more. The PhD should also understand that value statement as well. The PhD should not be held captive as cheap labor.

Nature concludes:

But there are signs that the issue is becoming less taboo. In September, a group of high-profile US scientists (Harold Varmus, Marc Kirschner, Shirley Tilghman and Bruce Alberts, colloquially known as 'the Quartet') launched Rescuing Biomedical Research, a website where scientists can make recommendations on how to 'fix' different aspects of the broken biomedical research system in the United States — the PhD among them. “How can we improve graduate education so as to produce a more effective scientific workforce, while also reducing the ever-expanding PhD workforce in search of biomedical research careers?” the site asks.

The change is simple. Let the PhDs know from the get go that they should, can, and must seek to "market" their talents, and not just their PhD research, and they they should seek jobs not short term low paid and low return task work. This is not just a problem in the bio area, it is quickly becoming a pandemic across many fields, engineering included. Why should any PhD in engineering do a post-doc? Get a job, use your skills, make something, and get out of the dream world of academia.     

DeVita, Cancer, and a Must Read

DeVita’s book, The Death of Cancer, is a personal recollection of one of the most well-known cancer specialists in the world. In a sense it is an Odyssey tale of a highly competent and prolific person who flows with his times and manages the Scylla and Charybdis of Government work. The book is well written and reflective of the man and his times. DeVita started out during the Vietnam era when any male graduating from Med School found themselves, unless otherwise excused, ready for immediate assignment to some military unit. Many of the top students were fortunate to get to go to NIH which was DeVita’s fate, and it was this flow of talent in the late 60s which made NIH and NCI one of the best institutions in the world. Thus the tale of DeVita and cancer starts here with NCI and a flow of excellent talent.

DeVita describes his work on the use of multiple chemotherapy regimens and the resistance from the likes of Farber in Boston, hardly an uncommon occurrence especially in Medicine. This was the MOPP therapy that most now know as a major breakthrough in Hodgkin’s. The discussion on how he and the team managed to persist and managed to go through the then significant administrative a bureaucratic complexities is amazing.

The discussion on his involvement in the “War on Cancer” and the political games is quite interesting especially for anyone who has not spent a tour of duty in Washington. There were games within games and DeVita was at times a willing participant but as see in the book and excellent observer. His description of the political gamesmanship is worth the read if nothing else. It is also worth the while for anyone seeking to grasp how Washington functions, and why it may work at times and often falls into total disarray.

On p. 159 I was interested to see the interlocutory between Benno Schmidt and Jim Watson while Watson was I gather performing one of his classic poses. This also is worth the read. I have had my students return from a talk by Watson and ask me: “Does he really think Physicians and Engineers are useless?” But I gather that is Watson, a scientist at heart.

On p 219 there is a great discussion of his time at MSKCC, a world renowned institution but at times falling behind in certain areas. DeVita states: “MSKCC had the potential to be the best cancer center in the world, it wasn’t” is a powerful statement and at times quite true. MSKCC has powerful backers and Board members and although it may try from time to time to be at the lead there is always the chance that it becomes insular. The lesson DeVita brings out here should be a warning for many such institutions.

On p 247 DeVita discusses the recent Hanahan and Weinberg paper on Cancer, a follow on to what the two authors had written in 2000. This is a paper on the hallmarks of cancer and is looked upon as a sine qua non in the literature. DeVita lauds it at length and rightly so. Yet what this paper also shows is that we have learned a great deal but the “War on Cancer” is just getting harder the more we learn. One could argue that the recent Hanahan and Weinberg paper albeit prescient and insightful lacks the depth on epigenetic factors which we are seeing more and more in cancers. The more that is learned the more complex the disease.

On p 253 DeVita discusses the inflammation relationship. We often ask what causes cancer and the more we understand inflammation the more we can see the nexus. This is a useful and important discussion as well.

On p 258 DeVita makes an interesting statement:

“In my opinion, when there is less than a 10% chance of the cancer recurring after a patient passes his or her cancer’s critical period, then the patient should be told, in all likelihood, he or she is cured.”

This is a powerful statement and one a physician with extensive clinical experience is wont to utter. However one should parse the statement. First, how does one determine a 10% chance? In prostate cancer we can perform a prostatectomy and monitor PPSA for several years and then see a met occur. When did the 10% level occur? Second, what is a critical period? How do we define it for each cancer? Then the catch phrase of “in all likelihood” is something the patient may or most likely not hear. Cancer patients often has selective hearing.

Overall the book is highly enlightening and a must read for anyone interested in the progression of cancer therapy. Also DeVita’s discussion of his battles with the FDA and Sen. Kennedy’s blatant interference with NCI if it in his opinion interfered with the FDA was quite interesting. DeVita bares the political quagmires of Washington and demonstrates that progress can often be made despite the Government overhead by dedicated and highly competent individuals.

An Excellent Contribution to the Literature

The book by Mydlo and Godec, Prostate Cancer, is an exceptionally good text for practicing urologists and residents to get an understanding of the current understanding of this disease, prostate cancer (PCa). PCa is a complex disorder, and is unlike many other cancers. On the one hand almost all PCas are indolent, namely the patient will most likely dies of something else, but the small percent that have an aggressive form die very rapidly. The primary tool for detection has been the PSA tests which were virulently attacked by the USPTF. It can be argued that the data they based their opinion on was flawed but we leave that for time to tell, unfortunately at the cost to the patient. The genetics of PCa is also highly complex.

Unlike so many other cancers where we can identify a specific target such as BRAF in melanoma, BRACA in breast cancer and ABL fusion in CML, PCa is a mass of speculative genetic changes. Also the treatment of PCa is becoming more problematic. The options are several; surgery, radiation, implants, and even “watchful waiting” which in a sense is let hope and see what happens. The problem is that PCa metastasis is insidious and unlike breast or melanoma the path is circuitous and uncertain.

This book is introduced at a time when all of these issues are facing the physician. The question is; what does the physician recommend as a course of action to a patient? All too often the patient presents with a diagnosed PCa and based upon the patient’s own investigations finds his path to a recommended therapy. Whether that is the best for this patient is usually uncertain.

On p3 the authors open with a direct assessment of the USPTF, one which I would strongly recommend reading for any practitioner. It is short, well written and on point. This in a sense sets this rest of the work in clear perspective; unlike the USPTF, this is a “what is the best for the patient” work.

The book is structured along standard lines.

The first several chapters deal with a wide variety of current issues such as the genetics, the androgen receptor issues, and fusion. All are done at a reasonably high level for the practitioner. This is clearly not a book on the detailed genetic issues associated with PCa. Chapter 5 is an interesting chapter since it discusses the issues of Gleason 6 and is it even a cancer. This is a compelling question since as we are discovering the genetic makeup is often more telling and that may mean the genetic makeup of the most aggressive cell. Chapter 6 is another significant chapter since it deals with HGPIN. HGPIN has for a decade or more been synonymous with a progression to PCa. However that is not inevitable. The interesting cases are those where there is a HGPIN at initial biopsy and then it disappears and never returns. The question then is; how significant a prognostic issue is HGPIN?

Chapter 11 discusses MRI imaging in localized PCa. MRI imaging is becoming more common and is becoming an element in integrated biopsies with real time ultrasound. This is a useful chapter for the urologist to become familiar with an imaging technique which will become a more integral part of diagnosis and prognosis. However as with all modalities it may add significantly to the costs and also may cause increased biopsy covers for what may not be significant observations.

Chapter 13 is an excellent discussion on PSA screening. PSA is a useful but sometimes problematic measure. PSA increases with prostate volume and age as well as with pathological changes. Differentiating them is complex. The physician must balance reasonableness with the risk of being too insensitive to the changes. Chapter 17 discusses hereditary PCa. This is mostly a discussion of genetic inheritances that result in PCa. However we also know that there is a strong correlation between first degree relative PCa and PCa in the patient. This is correlative and not causative, whereas what in in this chapter seems to be much more causative.

Chapters 26 thru 41 discuss the complexities of surgical treatment and the presentation is clear and up to date. Chapters 42 thru 48 discuss radiation therapies with equal presentation. Chapters 52 thru 57 discuss some advanced issue of PCa therapy. This includes several biologics as well as androgen therapies.

Chapter 66 is an interesting chapter in that it discusses new markers for diagnosis and prognosis. On the diagnosis side there are many ways to enhance PSA and related measures including PCA3. One of the recent tests such as 4K have seemed to be of some use in assessing the chance of there being PCa prior to biopsy. Although I have had experience with this test and positively specifically it is still as I write this not FDA approved. There are also almost a dozen genetic tests used on PCa cells after biopsy to ascertain a prognosis for subsequent aggressive potential. Many of these are still being tested but generally they also provide guidance. However the conundrum is using them for prognosis when the result is poor and there is no significant treatment available.

Overall this is an excellent up to date summary of PCa, its diagnosis, prognosis, treatment and the state of the science that surrounds it. It clearly meets the needs of the practitioner. Its weakness in my view, and that of one involved more deeply on the genetics side, is that it would have been helpful to have delved a bit more deeply in the genetics of PCa. Unlike many other cancers PCa is highly heterogeneous and it seems that each week one sees another several genes putatively involved. Thus one can appreciate perhaps avoiding this area since it may be out of date by publication.

This is an excellent and up to date text and a worthy addition to what is currently available.

The New Tsar

The book, The New Tsar by Myers, is a well done bio of Vladimir Putin. To set my observation space regarding this work, I was in Russia from 1995 thru 2004, in Saint Petersburgh and Moscow, starting my telecommunications company, and with partners who were from the same world as Putin. These folks knew me since in the 70s I had been part of the US Comprehensive Test Ban Treaty talks and had one on one contact with various Russians. I managed a bit of Russian language, adequate to get about, and even joke after a few vodkas. Thus I had been closely aware of Russia, the Russians, and the KGB world. Unlike most Americans I had no larger company backing and I needed in country partners, many of whom are covered in Myers tale. I saw Moscow via the Metro, the streets, the stores, the homes. I saw vodka used to brush teeth because the water is so infested it is barely adequate to flush toilets. Yet the streets looked like Tokyo at night, a change which occurred in less than ten years.

Myers takes on a journey which has as its focus Putin, but for all purposes it is a journey on the change of Russia from Communism to what it is today. In a sense, the Orthodox Church has replaced the Communist Party for the masses, a milder means of establishing the mandated role of the rulers. This comes out in Myers work by the telling tale of Putin being baptized as a child. Myers did not really explore the depths of this ongoing cooperation but he does provide certain pieces. Myers follows Putin and attempts to give some depth to the many by his movement from young KGB “employee”, to the accidental head of the FSB (formerly the KGB) and then to President. In a sense Putin’s life is almost Forest Gump like, just being there when the bus went by and getting on to see where it took him next.

Unlike a Tsar, one who was born to “greatness” and knew it by birth, Putin just happened to be at the right place at the right time with the right attitude. The appointment of Putin as President by Yeltsin was a turning moment, for up until that moment he was an effective administrative functionary, but then he was thrown headlong into the top leadership slot. His KGB past was his backstop. His trusted friends, if any, were from that time and space. Key among them was Sergei Ivanov, a KGB general and longtime associate. Ivanov flows in and out of Myers book but it would have been worthwhile to have explored him in more depth.

The discussion by Myers concerning Putin and Bush is also telling. At first, after 9/11, there was a bond, but as the US managed to take its aggressive single handed approach to Iraq that bond fell apart. Putting understood Iraq, albeit from afar via Afghanistan and Russia’s disaster. Bush did not, and his team also did not. Thus, the quagmire. There is also the discussion on boundaries and NATO and Russia’s near abject terror of a NATO encroachment. Why the US never truly understood the need for Russia to have a buffer is amazing. Russia just needs neutral borders, ones not militarily aligned with the West.

Myers does a reasonable job on Putting I and Putin II. Namely Putin I is the accidental president. This is a period of his ascending to the highest rank. Much of this time he is learning and expanding. Then after his hiatus, he is now Putin II, no longer accidental, but deliberate and with a depth of team players to make him untouchable in Russia. The problem is when we see Putin II we see in many ways the old KGB tactics. Myers discusses many of the allegations of assassinations and corruption.

The book is exceptionally well written and is a major contribution to the understanding of Putin. But the book also demonstrates that Putin II is a moving target and evolving and expanding player on the world stage, a man who is much more comfortable in his new role rather than the accidental presidency that pushed him to the forefront.

If Myers’ book does anything, it should enlighten some in Washington as to whom they are dealing with. He is a Russian, has a Russian mind, and in a sense a Russian soul. One must understand Russia at least a little to understand Putin. Kennan had such an understanding. Very few have had such in the US since then.

CRISPR and the Sears Catalog

In a recent paper by Graham and Root[1] at MIT/Broad the authors provide an interesting list of CRISPR facilitators. It is akin in many ways to the old Sear catalog. For folks who may be much too young to remember the Sear catalog, if one lived  quite a distance from a large store, or if you just wanted to spend time looking at what you could get, Sear sent out 3” thick tissue paper catalogs. They had page after page of “stuff”, and Amazon before Amazon.

In the paper by Graham and Root one finds a much thinner version of this for CRISPRs, but with activating the URLs attached one can get the equivalent feeling. A complete set of Sears Craftsman tools, but for assembling genes via a piece by piece method.

Recall that CRISPR is that targeting sequence of an RNA to attach to a specific part of a gene so that the Cas9 protein can cut the gene at the end of the PAM sequence. Also recall that we can use different proteins from Cas9 to make offset cuts. Cas9 makes cuts opposite one another which often leads to possible reconnection problems.

The CRISPR-Cas9 combination is but one of many that can apparently be used. Changing Cas9 for other proteins lead to altered cutting mechanisms which we have discussed previously. There are in the Graham and Root paper four fundamental applications. They are:

1. Cutting or Knock Out (KO) where a gene sequence is cut from a chromosome.

2. Pasting or Knock In (KI) where a gene sequence is added.

3. Inhibition where a gene expression is inhibited by creating a block to a transcription factor.

4. Activation where an activator is effected by the CRISPR Cas9 action.

In some sense types 3 and 4 are also done by methylation or indirectly via miRNAs.  

Graham and Root first discuss design factors and they state:

The following considerations and guidance apply to many types of CRISPR-based experiments:

The delivery method for Cas9 and sgRNAs can be transfection or transduction. Viral transduction is required for pooled screens. More consistent activity can be provided by selection of Cas9-expressing, CRISPR-active cells. CRISPR activity can be variable across cell types and should be experimentally confirmed case by case.  

The delivery mechanism is a critical factor. How does one get the combos into a cell? Some recent work indicated that a cell can make its own Cas9 and then inject the CRISPR. The challenge is also targeting specific cells. In some areas one has looked at this approach almost as a weaponized system and the delivery mechanism is as critical as the actions themselves.

One should select sgRNAs to maximize the likelihood of high activity and specificity. The current state of knowledge provides useful guidance for selecting target sites and sgRNAs, but predictions of efficacy and especially of specificity are currently far from perfect. Table 1 describes tools now available to assist in this process. New tools and strategies are arising frequently as the understanding of CRISPR technology improves.  

The sgRNAs used to select the gene sequences are not always that selective and have less than perfect specificity. This can be complicated in a wild type environment where the genes may be present in a certain large percentage but intra-species variations are possible.

Multiple sgRNAs per target gene (typically ranging from three to eight) should be employed wherever possible, first, to provide more opportunities to achieve the desired on-target modification and, second, to evaluate concordance of the phenotypic effects of multiple independent reagents to prioritize results most likely to be on-target — that is, causally linked to the intended genetic perturbation.  

Toolkits for better targeting and specificity are essential.

Validation of genetic models and phenotypes is essential. Confirmation of on-target efficacy is important for selecting good cell clones to use for subsequent experiments and to establish the specific gene edits produced. Experimental assessment of off-target effects of sgRNAs can also inform clone selection.

The targeting is still not perfect. It is also not clear what effects such epigenetic factors such as methylation will have.

They do discuss the usefulness of this technique in examining the functions of genes by KO analyses. However as we learn more about genes we see that are a mass of interconnected strings and the one gene one function model of Mendel has outlived its usefulness.

They conclude by stating:

One major goal is to achieve more efficient, predictable editing. If it were possible to convert every cell in a population to the desired genotype, the painstaking work of selecting and characterizing individual clones would be reduced or eliminated. This would make it feasible to engineer large numbers of clonal cell lines, or even to engineer specific alleles at a screening scale. It would also make it far more efficient to produce cells with multiple edits. One approach is to re-engineer Cas9 for desirable characteristics, including altered PAM sequences, better packaging into virus, better binding and cutting efficacy and higher specificity. The hunt is also under way for better type II Cas9 proteins or other type II CRISPR proteins that might possess performance advantages, or to provide altogether new activities. The adoption of new CRISPR systems might necessitate new studies to determine their on- and off-target behavior and ideal design parameters. 

This paper is well worth using since it is a balance of what is achieveable and provides and exceptionally useful tool box for those working in the area. The only issue is that the area is changing so rapidly that the tool box may have to be updated frequently.

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[1] http://www.genomebiology.com/2015/16/1/260 Graham and Root, Resources for the design of CRISPR gene

editing experiments, Genome Biology (2015) 16:260

What's Old is New Again

In an article about an Estonian company the CSM states:

 Velmenni, an Estonian tech company that has installed Li-Fi in its offices, says that the technology has achieved speeds of up to 224 gigabits per second in the lab and 1 gigabit per second in real life, where transmissions must contend with other factors such as movement and interference from other light sources. An office or industrial park could be outfitted with smart LED bulbs that could send data and provide illumination simultaneously

Well 50 years ago we called this optical communications. I even did a PhD in the area back then and a colleague connected two mountains in New Hampshire, Wildcat and  Mt Washington, optically back in the 60s.

One of the problems with optical is that it does not bend. Now the CSM states:

There’s a catch, though: Because light can’t pass through walls or other obstacles, a Li-Fi access point can cover only a single room. That means multiple smart LEDs will be needed to cover an apartment or a house with speedy wireless coverage. But on the other hand, wireless interference will be greatly reduced.

WiFi does not go "through" walls as well. It does refract and it does reflect, thus having multipath to work with, something I did some 40+ years ago.

So what is new here? In my opinion not much. So why the outbursts from the media? I guess they just do not understand. It does fill up pages.